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EPILEPSY AND OTHER cap height base of text SEIZURE DISORDERS
In contemporary society, the frequency and importance of epilepsy logic disease that demands the employment of special diagnostic can hardly be overstated. From the epidemiologic studies of Hauser and therapeutic measures, as in the case of a brain tumor. and colleagues, one may extrapolate an incidence of approximately A more common and less grave circumstance is for a seizure 2 million individuals in the United States who are subject to epi- to be but one in an extensive series recurring over a long period of lepsy (i.e., chronically recurrent cerebral cortical seizures) and pre- time, with most of the attacks being more or less similar in type. dict about 44 new cases per 100,000 population occur each year. In this instance they may be the result of a burned-out lesion that These figures are exclusive of patients in whom convulsions com- originated in the past and remains as a scar. The original disease plicate febrile and other intercurrent illnesses or injuries. It has also may have passed unnoticed, or perhaps had occurred in utero, at been estimated that slightly less than 1 percent of persons in the birth, or in infancy, in parts of the brain inaccessible for exami- United States will have epilepsy by the age of 20 years (Hauser nation or too immature to manifest signs. It may have affected a and Annegers). Over two-thirds of all epileptic seizures begin in very small or “silent” area in a mature brain. The increasingly re- childhood (most in the first year of life), and this is the age period fined techniques of magnetic resonance imaging (MRI) are now when seizures assume the widest array of forms. The incidence beginning to reveal small zones of cortical dysplasia and hippo- increases again slightly after age 60. In the practice of pediatric campal sclerosis, both of which tend to be epileptogenic. Patients neurology, epilepsy is one of the most common disorders. The with such long-standing lesions probably make up the majority of chronicity of childhood forms and their persistence in patients of those with recurrent seizures but are necessarily classified as having all ages adds to their importance. For all these reasons, every phy- “idiopathic” or “cryptogenic epilepsy,” because it is often impos- sician should know something of the nature of seizure disorders sible to ascertain the nature of the original disease and the seizures and their treatment. It is, however, notable that in striking contrast may be the only sign of brain abnormality. to the many treatments available for epilepsy, as pointed out by There are other types of epilepsy for which no pathologic basis J. Engle, 80 to 90 percent of epileptics in the developing world has been established and for which there is no apparent underlying never receive treatment. cause except perhaps a genetic one. These epilepsies have been Epilepsy was in the past defined as an intermittent derange- referred to as primary. Included in this category are hereditary ment of the nervous system due to “an excessive and disorderly forms, such as certain generalized tonic-clonic (grand mal) and discharge of cerebral nervous tissue on muscles.” This was the “absence” seizure states. Some authors (Lennox and Lennox; For- postulate, in 1870, of Hughlings Jackson, the eminent British neu- ster) have reserved the term idiopathic for recurrent seizures of rologist, and modern electrophysiology offers no evidence to the these types. contrary. The discharge may result in an almost instantaneous loss of consciousness, alteration of perception or impairment of psy- CLASSIFICATION OF SEIZURES chic function, convulsive movements, disturbance of sensation, or some combination thereof. A terminologic difficulty arises Seizures have been classified in several ways: according to their from the diversity of the clinical manifestations. The term con- supposed etiology, i.e., idiopathic (primary) or symptomatic (sec- vulsion,referringasitdoestoanintenseparoxysmofinvoluntary ondary); their site of origin; their clinical form (generalized or fo- repetitive muscular contractions, is inappropriate for a disorder cal); their frequency (isolated, cyclic, or repetitive, or the closely that may consist only of an alteration of sensation or conscious- spaced sequence of status epilepticus); or their electrophysiologic ness. Seizure is preferable as a generic term, since it embraces a correlates. A distinction must be made between the classification diversity of paroxysmal events and also because it lends itself to of seizures (the clinical manifestations of epilepsy: grand mal, petit qualification. The term motor or convulsive seizure is therefore mal, myoclonic, partial, and others), considered below, and the not tautologic, and one may likewise speak of a sensory seizure classification of the epilepsies, or epileptic syndromes, which are or psychic seizure.Thewordepilepsy is derived from Greek disease constellations, most of which may manifest several seizure words meaning “to seize upon” or a “taking hold of.” Our pred- types. These are discussed later in the chapter. ecessors referred to it as the “falling sickness” or the “falling The classification to be followed here was first proposed by evil.” Although a useful medical term to denote recurrent sei- Gastaut in 1970 and was then refined repeatedly by the Commis- zures, the words epilepsy and epileptic still have unpleasant con- sion on Classification and Terminology of the International League notations to the laity and should be used advisedly in dealing with Against Epilepsy (1981). This classification, based mainly on the patients. clinical form of the seizure and its electroencephalographic (EEG) Viewed in its many clinical contexts, the first solitary seizure features, has been adopted worldwide and is generally referred to or brief outburst of seizures may occur during the course of many as the International Classification. A modified version of it is re- medical illnesses. It indicates that the cerebral cortex has been af- produced in Table 16-1. fected by disease, either primarily or secondarily. Convulsive sei- The strength of the International Classification lies in its easy zures by their nature, if repeated every few minutes, as in status applicability to patients with epilepsy and its universal adoption. epilepticus, may threaten life. Equally important, a seizure or a The main value of classifying a seizure by its clinical and EEG short series of seizures may be the manifestation of an ongoing neuro- features is the reasonable predictability of response to specific med- stand
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cap height Table 16-1 ing frequency and severity of this group of disorders with age re- base of text International classification of epileptic seizures flects the accumulation of focal insults from trauma, strokes, and I. Generalized seizures (bilaterally symmetrical and without lo- other damage. cal onset) Partial or focal seizures are further classified as simple when A. Tonic, clonic, or tonic-clonic (grand mal) consciousness is undisturbed and complex when consciousness is B. Absence (petit mal) altered or impaired. Simple partial seizures are further classified 1. With loss of consciousness only according to their main clinical manifestations—motor, sensory, 2. Complex—with brief tonic, clonic, or automatic autonomic, or psychic. When one of these subjective manifesta- movements tions precedes the progression of the attack to a loss of conscious- C. Lennox-Gastaut syndrome ness, it is referred to as an aura and has commonly been regarded D. Juvenile myoclonic epilepsy as a premonitory sign or warning of the impending seizure. In re- E. Infantile spasms (West syndrome) ality, the aura represents the initial phase of a focal seizure; in some F. Atonic (astatic, akinetic) seizures (sometimes with myo- instances it may constitute the entire epileptic attack. clonic jerks) Generalized seizures are of two types—convulsive and non- II. Partial, or focal, seizures (seizures beginning locally) convulsive. The common convulsive type is the tonic-clonic (grand A. Simple (without loss of consciousness or alteration in mal) seizure. Less common is a purely tonic, purely clonic, or psychic function) clonic-tonic-clonic generalized seizure. The classic nonconvulsive 1. Motor–frontal lobe origin (tonic, clonic, tonic-clonic; generalized seizure is the brief lapse of consciousness or absence jacksonian; benign childhood epilepsy; epilepsia par- (petit mal); included also under this heading are minor motor phe- tialis continua) nomena such as brief myoclonic, atonic, or tonic seizures. 2. Somatosensory or special sensory (visual, auditory, ol- The classification of seizures and of the epilepsies is con- factory, gustatory, vertiginous) stantly being modified. In one of the latest versions, the so-called 3. Autonomic syndromic classification (Epilepsia 30:389, 1989), an attempt has 4. Pure psychic been made to incorporate all of the seizure types and epileptic syn- B. Complex (with impaired consciousness) dromes and to categorize them not only as partial and generalized 1. Beginning as simple partial seizures and progressing to but also according to their age of onset, their primary or secondary impairment of consciousness nature, the evidence of cortical loci of the epileptogenic lesions, 2. With impairment of consciousness at onset and the many clinical settings in which they occur. This classifi- III. Special epileptic syndromes cation is semantically difficult and, in our view, too complicated A. Myoclonus and myoclonic seizures as yet for general clinical application. Since many epileptic syn- B. Reflex epilepsy dromes share overlapping features, it is often not possible to fit a C. Acquired aphasia with convulsive disorder newly diagnosed case of epilepsy into a specific category in this D. Febrile and other seizures of infancy and childhood new classification (Manford et al). The commission is engaged in E. Hysterical seizures an extensive revision of terminology and classification in the field of epilepsy. Until this revision is widely adopted, we propose to begin our discussion with the 1981 classification of seizures, with certain modifications and additions, to be followed by a consider- ications and to some extent in prognosis. Basically, this classifi- ation of a number of well-defined epilepsies and epileptic syn- cation divides seizures into two types—partial, in which a focal dromes. or localized onset can be discerned, and generalized, in which the In the discussions that follow, the various types of seizures seizures appear to begin bilaterally. are viewed largely in the context of the age at which they occur. It is also useful clinically and etiologically to separate epilep- An approximation of the distribution of the seizure types for each sies that originate as truly generalized electrical discharges in the age epoch, obtained and aggregated from several sources, is shown brain from those which spread secondarily from a focus to become in Fig. 16-1. generalized. The primary generalized epilepsies are a group of There has also been substantial progress in defining the mo- somewhat diverse, age-dependent phenotypes that are character- lecular basis of familial and hereditary epilepsies over the last dec- ized by generalized 2.5- to 4-Hz bifrontally predominant spikes or ade; it is highly likely that these new insights will lead to further polyspike-and-slow-wave discharges that arise without underlying modification of both the clinical classifications and the therapeutic structural abnormalities. In most instances, these individuals have management of the epilepsies (see further on). normal intelligence. What is most significant is that a genetic com- ponent underlies many of these disorders (see below). By contrast, GENERALIZED SEIZURES seizures that begin locally and evolve into generalized tonic-clonic seizures, termed secondary generalized seizures, generally have no The Generalized Tonic-Clonic Seizure such genetic component and are usually the result of underlying (Grand Mal) brain disease, either acquired or due to congenital malformations or metabolic defects. Quite often, the initial focal phase is missed, As has already been pointed out, it is important, whenever possible, leading to misdiagnosis. Individuals with secondary generalized to distinguish between a primary (generalized) type of seizure, with epilepsies tend to have more diffuse brain dysfunction and may widespread EEG abnormalities at the onset, and a secondarily gen- have a progressive course. These seizures may be of different types, eralized type, which begins as a focal or partial seizure and then including atonic, myoclonic, and tonic-clonic seizures. An increas- becomes generalized. short
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cap height The patient sometimes senses Type of seizure base of text the approach of a seizure by one of 60 Complex partial several subjective phenomena (a 50 prodrome). For some hours, the pa- Simple partial 40 Partial, unclassified tient may feel apathetic, depressed, Generalized tonic-clonic 30 irritable, or, very rarely, the oppo- Absence site—ecstatic. One or more my- 20 Myoclonic oclonic jerks of the trunk or limbs 10 Generalized, other on awakening may herald a seizure Unknown, multiple 0 later in the day. In more than half Percent of incident cases 0–14 15–34 36–64 >65 the cases, there is some type of Years movement for a few seconds before Figure 16-1. The distribution of the main types of epilepsy by age. Apparent is the overrepresentation of absence consciousness is lost (turning of and myoclonic seizures in childhood and of complex partial seizures in older individuals. (Adapted from Hauser the head and eyes or whole body or and Annegers and the texts of Engel and of Pedley.) intermittent jerking of a limb), al- though the patient fails to form a memory of this and such information is obtained only from an turbed, he becomes drowsy and falls asleep, sometimes for several observer. Abdominal pains or cramps, a sinking, rising, or gripping hours, then sometimes awakens with a pulsatile headache. When feeling in the epigastrium, pallor or redness of the face, throbbing fully recovered, such a patient has no memory of any part of the headache, constipation, or diarrhea have also been given prodro- spell but knows that something has happened because of the strange mal status, but we have not found them consistently enough to be surroundings (in ambulance or hospital); the obvious concern of helpful. those around him; and a sore, bitten tongue and aching muscles Most often, the seizure strikes “out of the blue,” i.e., without from the violent contractions. The latter, if violent enough, may warning, beginning with a sudden loss of consciousness and fall to crush a vertebral body or result in a serious injury; a fracture, peri- the ground. The initial motor signs are a brief flexion of the trunk, orbital hemorrhages, subdural hematoma, or burn may have been an opening of the mouth and eyelids, and upward deviation of the sustained in the fall. eyes. The arms are elevated and abducted, the elbows semiflexed, Each of these phases of the generalized tonic-clonic seizure and the hands pronated. These are followed by a more protracted has its characteristic EEG accompaniment. Initially, movement ar- extension (tonic) phase, involving first the back and neck, then the tifacts obscure the EEG changes; sometimes there are repetitive arms and legs. There may be a piercing cry as the whole muscu- spikes or spike-wave discharges lasting a few seconds, followed lature is seized in a spasm and air is forcibly emitted through the by an approximately 10-s period of 10-Hz spikes. As the clonic closed vocal cords. Since the respiratory muscles are caught up in phase asserts itself, the spikes become mixed with slow waves and the tonic spasm, breathing is suspended, and after some seconds then the EEG slowly assumes a polyspike-and-wave pattern. When the skin and mucous membranes may become cyanotic. The pupils all movements have ceased, the EEG tracing is nearly flat for a are dilated and unreactive to light. The bladder may empty at this variable time, and then the brain waves resume their preseizure stage or later, during the postictal coma. This is the tonic phase of pattern. the seizure and lasts for 10 to 20 s. Convulsions of this type ordinarily come singly or in groups There then occurs a transition from the tonic to the clonic of two or three and may occur when the patient is awake and active phase of the convulsion. At first there is a mild generalized tremor, or during sleep, or frequently when falling asleep or awakening. which is, in effect, a repetitive relaxation of the tonic contraction. Some 5 to 8 percent of such patients will at some time have a It begins at a rate of eight per second and coarsens to four per prolonged series of such seizures without resumption of conscious- second; then it rapidly gives way to brief, violent flexor spasms ness between them; this is called convulsive status epilepticus and that come in rhythmic salvos and agitate the entire body. The face demands urgent treatment. Sometimes the first outburst of seizures becomes violaceous and contorted by a series of grimaces, and takes the form of convulsive status. often the tongue is bitten. Autonomic signs are prominent: the pulse Few clinical states closely simulate a grand mal convulsion, is rapid, blood pressure is elevated, pupils are dilated, and saliva- but several are worthy of mention. One is a clonic jerking of the tion and sweating are abundant; bladder pressure may increase six- extended limbs (usually less severe than those of a grand mal sei- fold during this phase. The clonic jerks decrease in amplitude and zure) that occurs with vasodepressor syncope or a Stokes-Adams frequency over a period of about 30 s. The patient remains apneic attack. In contrast to an epileptic type of EEG, the brain waves are until the end of the clonic phase, which is marked by a deep in- slow and flat during the jerking movements. A rarer phenomenon spiration. Instead of the whole dramatic sequence described above, that may be indistinguishable from a generalized convulsion occurs the seizures may be abbreviated or limited in scope by anticon- as part of basilar artery occlusion (Ropper). This presumably has vulsive medications. its basis in ischemia of the corticospinal tracts in the pons; a similar In the terminal phase of the seizure, all movements have ended ischemic mechanism in the cortex has been invoked for “limb- and the patient lies still and limp, in a deep coma. The pupils, equal shaking TIAs” (transient ischemic attacks), in which there are clo- or unequal, now begin to contract to light. Breathing may be quiet nic movements of one limb or one side of the body during an or stertorous. This state persists for several minutes, after which episode of cerebral ischemia. Hysterical (nonepileptogenic, “psy- the patient opens his eyes, begins to look about, and is obviously chogenic”) seizures, as discussed further on, are often difficult to bewildered and confused and may be quite agitated. The patient distinguish from a true seizure. Rarely, in adults, an attack of panic may speak and later not remember anything that he said. Undis- (page 438) or the rare entity of rapid-eye-movement (REM) sleep short
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cap height behavior disorder (page 343) may resemble a seizure. In infants, a which the EEG abnormalities are less regularly of a 3-per-second base of text breath-holding spell may resemble the tonic phase of a generalized spike-and-wave type (they may occur at the rate of 2 to 2.5 per seizure. second or take the form of 4- to 6-Hz polyspike-and-wave com- plexes). Atypical petit mal is a term that was coined to describe Idiopathic Nonconvulsive Seizures long runs of slow spike-and-wave activity, usually with no apparent (Absence, Petit Mal) loss of consciousness. External stimuli such as asking the patient to answer a question or to count will interrupt the run of abnormal In contrast to major generalized seizures, absence seizures (for- EEG activity. merly referred to as petit mal or pykno-epilepsy) are notable for About one-third of children with absence attacks will, in ad- their brevity and the paucity of motor activity. Indeed, they may dition, display symmetrical or asymmetrical myoclonic jerks with- be so brief that the patients themselves are sometimes not aware out loss of consciousness, and about half will also at some time of them; to an onlooker, they resemble a moment of absentmind- have major generalized (tonic-clonic) convulsions. As described edness or daydreaming. The attack, coming without warning, con- further on, a common and relatively benign variety of myoclonic sists of a sudden interruption of consciousness, for which the seizure occurs in late childhood and adolescence (juvenile myo- French word absence (“not present,” “not in attendance”) has been clonic epilepsy). retained. The patient stares and briefly stops talking or ceases to In sharp contrast to the aforementioned epilepsies is a form respond. Only about 10 percent of such patients are completely that has its onset between 2 and 6 years of age and is characterized motionless during the attack; in the remainder, one observes a brief by atonic, or astatic, seizures (i.e., falling attacks), often succeeded burst of fine clonic movements of the eyelids, facial muscles, or by various combinations of minor motor, tonic-clonic, and partial fingers or synchronous movements of both arms at a rate of three seizures and by progressive intellectual impairment in association per second. This rate corresponds to that of the EEG abnormality, with a distinctive, slow (1- to 2-Hz) spike-and-wave EEG pattern. which takes the form of a generalized three-per-second spike-and- This is the Lennox-Gastaut syndrome. Often it is preceded in earlier wave pattern (Fig. 2-3E, page 26). Minor automatisms—in the life by infantile spasms, a characteristic EEG picture (3-Hz “hyp- form of lip-smacking, chewing, and fumbling movements of the sarrhythmia”), and an arrest in mental development, a triad some- fingers—are common during an attack but do not assume promi- times referred to as the West syndrome (see further on). The early nence. Postural tone may be slightly decreased or increased, and onset of atonic seizures with abrupt falls, injuries, and associated occasionally there is a mild vasomotor disorder. As a rule, such abnormalities nearly always has a grave implication—namely, the patients do not fall; they may even continue such complex acts as presence of serious neurologic disease. Prematurity, perinatal in- walking or riding a bicycle. After 2 to 10 s, occasionally longer, jury, and metabolic diseases of infancy are the most common un- the patient re-establishes full contact with the environment and re- derlying conditions. This is essentially a symptomatic generalized sumes preseizure activity. Only a loss of the thread of conversation epilepsy, in contrast to the foregoing idiopathic types. The Lennox- or the place in reading betrays the occurrence of the momentary Gastaut syndrome may persist into adult life and is one of the most “blank” period (the absence). In many such patients, voluntary hy- difficult forms of epilepsy to treat. perventilation for 2 to 3 min is an effective way of inducing absence The notion that absence, myoclonic, and akinetic seizures con- attacks. stitute a petit mal triad, as originally proposed by Lennox, has been Typical absence seizures constitute the most characteristic ep- generally abandoned. Akinesia (motionlessness) is not unique to ilepsy of childhood; rarely do the seizures begin before 4 years of any seizure type. The typical absence, with or without myoclonic age or after puberty. Another attribute is their great frequency jerks, rarely causes the patient to fall and should be considered a (hence the old term pykno, meaning “compact” or “dense”). As separate entity because of its relative benignity. many as several hundred may occur in a single day, sometimes in bursts at certain times of the day. Most often they relate to periods Myoclonic Seizures of inattention and may appear in the classroom when the child is sitting quietly rather than participating actively in his lessons. If The phenomenon of myoclonus has already been discussed in frequent, they may disturb attention and thinking to the point that Chap. 6, where the relationship to seizures was indicated. Char- the child’s performance in school is impaired. Such attacks may acterized by a brusque, brief, muscular contraction, some myo- last for hours with no interval of normal mental activity between clonic jerks are so small as to involve only one muscle or part of them—so-called absence or petit mal status. Small, subtle three- a muscle; others are so large as to implicate a limb on one or both per-second myoclonic movements are the only motor display sides of the body or the entire trunk musculature. Many are brief, (myoclonic petit mal), and are accompanied by a continuous three- lasting 50 to 100 ms. They may occur intermittently and unpre- per-second spike-wave abnormality in the EEG. Most cases of ab- dictably or present as a single jerk or a brief salvo. sence status have been described in adults with frontal lobe epilepsy As mentioned earlier, an outbreak of several small, rhythmic (see below). Such attacks may begin or end with a generalized myoclonic jerks may appear with varying frequency as part of ab- tonic-clonic seizure or a burst of seizures. sence seizures and as isolated events in patients with generalized Absence may be the only type of seizure during childhood. clonic-tonic-clonic or tonic-clonic seizures. As a rule, these types The attacks tend to diminish in frequency in adolescence and then of myoclonus are quite benign and respond well to medication. In often disappear, only to be replaced in many instances by major contrast, disseminated myoclonus (polymyoclonus), having its on- generalized seizures. set in childhood, raises the suspicion of acute viral encephalitis, the myoclonus-opsoclonus-ataxia syndrome of Kinsbourne, lith- Absence or Petit Mal Variants To be distinguished from typical ium or other drug toxicity, or, if lasting a few weeks, subacute absence seizures are varieties in which the loss of consciousness is sclerosing panencephalitis. Chronic progressive polymyoclonus short less complete or in which myoclonus is prominent, and others in with dementia characterizes the group of juvenile lipidosis, Lafora- stand
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cap height type familial myoclonic epilepsy, certain mitochondrial disorders, Table 16-2 base of text or other chronic familial degenerative diseases of undefined type Common seizure patterns (paramyoclonus multiplex of Friedreich, dyssynergia cerebellaris myoclonica of Ramsay Hunt). In middle and late adult years, dis- CLINICAL TYPE LOCALIZATION seminated myoclonus joined with dementia usually indicates the Somatic motor presence of so-called Creutzfeldt-Jakob disease (page 653) and Jacksonian (focal motor) Prerolandic gyrus rarely of Alzheimer disease. A few late-onset cases of Lafora dis- Masticatory, salivation, Amygdaloid nuclei, opercular ease have been reported (Messouak et al), but this remains mainly speech arrest a childhood process, autosomal recessive in transmission, charac- Simple contraversive Frontal terized by a triad of progressive dementia, myoclonus, and episodes Head and eye turning Supplementary motor cortex of generalized seizures, some of which are visual in nature. Intra- associated with arm neuronal cortical inclusions of amyloid are found, and similar in- movement or athetoid- clusions are found in muscle, liver, and skin (polyglucosan body dystonic postures disease is another process associated with these changes). My- Somatic and special sensory (auras) oclonus is usually the main manifestation of juvenile myoclonic Somatosensory Contralateral postrolandic epilepsy, as discussed below. Uremia at any age gives rise to my- Unformed images, lights, Occipital oclonus, twitching, and sometimes seizures. The large number of patterns diseases causative of myoclonus and seizure disorders are dis- Auditory Heschl’s gyri cussed in Chaps. 33, 37, and 39. Vertiginous Superior temporal Olfactory Mesial temporal Juvenile Myoclonic Epilepsy This is the most common form of Gustatory Insula idiopathic generalized epilepsy in older children and young adults. Visceral: autonomic Insular-orbital-frontal cortex It begins in adolescence, typically about age 15, with a range that Complex partial seizures essentially spans all of the teenage years. The patient comes to Formed hallucinations Temporal neocortex or attention because of a generalized seizure, often upon awakening amygdaloid-hippocampal or because of myoclonic jerks in the morning that involve the entire complex body; sometimes absence seizures are prominent. The family re- Illusions ports that the patient has occasional myoclonic jerks of the arm Dyscognitive experiences and upper trunk that become prominent with fatigue, during early (de´ja` vu, dreamy states, stages of sleep, or after alcohol ingestion. A few patients in our depersonalization) experience have had only the myoclonic phenomena and rare ab- Affective states (fear, Temporal sence seizures that persisted unnoticed for years. The EEG char- depression, or elation) acteristically shows bursts of 4- to 6-Hz irregular polyspike activ- Automatism (ictal and Temporal and frontal ity. A linkage has been established to chromosome 6 in some cases postictal) of this illness and in some other forms of juvenile-onset epilepsy, Absence Frontal cortex, amygdaloid- but no mendelian pattern of inheritance has been established. The hippocampal complex, disorder does not impair intelligence and tends not to be progres- reticular-cortical system sive, but a proclivity to infrequent seizures usually continues Bilateral epileptic myoclonus Reticulocortical, frontocentral throughout life. Valproic acid in particular and some other anti- convulsants have been highly effective in eliminating the seizures SOURCE: Modified by permission from Penfield and Jasper. and myoclonus; they should be continued indefinitely. Frontal Lobe Partial Seizures (Focal PARTIAL OR FOCAL SEIZURES Motor and Jacksonian Seizures) As indicated earlier, the International Classification divides all sei- Focal or partial motor seizures are attributable to a discharging zures into two types—generalized (described above), in which the lesion of the opposite frontal lobe. The most common type, origi- clinical and EEG manifestations indicate bilateral and diffuse ce- nating in the supplementary motor area, takes the form of a turning rebral cortical involvement from the onset, and focal or partial movement of the head and eyes to the side opposite the irritative (more recently termed localization-related), in which the seizure is focus, often associated with a tonic contraction of the trunk and often the product of a demonstrable focal lesion or EEG abnor- limbs on that side. This may constitute the entire seizure, or it may mality in some part of the cerebral cortex (or perhaps in the dien- be followed by generalized clonic movements; the extension of the cephalon). As noted, partial seizures vary with the locale of the seizure may occur just before or simultaneously with loss of con- lesion and are conventionally divided into two groups, simple and sciousness. On the other hand, a lesion in one frontal lobe may give complex, depending on whether consciousness is retained or im- rise to a major generalized convulsion without an initial turning of paired. Simple partial seizures most often arise from foci in the the head and eyes. It has been postulated that in both types of sensorimotor cortex. Complex partial seizures most often have their seizure, the one with and the one without turning movements, there focus in the temporal lobe on one side or the other, but a frontal is an immediate spread of the discharge from the frontal lobe to localization is also well known. The sites of the offending lesions integrating centers in the thalamic or high midbrain reticular for- and the types of seizures to which they give rise are listed in Table mation, accounting for the loss of consciousness.
16-2. These relationships are so helpful in diagnosis that they Seizures that begin with forceful, sustained deviation of the short should be familar to all neurologists. head and eyes, and sometimes of the entire body, are referred to as stand
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cap height versive or adversive. Since the turning movements are usually to those confined to the premotor cortex (area 6), tonic contractions base of text the side opposite the irritative focus (sometimes to the same side), of the contralateral arm, face, neck, or all of one side of the body. contraversive and ipsiversive, respectively, would be preferable Tonic elevation and extension of the contralateral arm (“fencer’s terms. Nonforceful, unsustained, or seemingly random lateral head posture”) and choreoathetotic and dystonic postures have been as- movements during the ictus do not have localizing value. The same sociated with high medial frontal lesions (area 8 and supplementary is true for the head and eye turning that occurs at the end of the motor cortex), as have complex, bizarre, and flailing movements generalized tonic-clonic phase of versive seizures (Wylie et al). of a contralateral limb, but this always raises the suspicion of hys- Contraversive deviation of only the head and eyes can be induced terical seizure. Perspiration and piloerection occur occasionally in most consistently by electrical stimulation of the superolateral fron- parts of the body involved in a focal motor seizure, suggesting that tal region (area 8), just anterior to area 6 (see Fig. 22-1). Less these autonomic functions have a cortical representation in or ad- dependably, the same movements can be obtained by stimulating jacent to the rolandic area. Focal motor and jacksonian seizures the more anterior portions of the frontal cortex, or the supplemen- have essentially the same localizing significance. tary motor area, and the temporal or occipital cortex—presumably Seizure discharges arising from the cortical language areas through propagation of the ictal discharge to the frontal contra- may give rise to a brief aphasic disturbance (ictal aphasia) and versive area. In seizures of temporal lobe origin, early in the sei- ejaculation of a word, or, more frequently, a vocal arrest. Ictal zure, there may be head turning ipsilaterally followed by forceful, aphasia is usually succeeded by other focal or generalized seizure contraversive head (and body) turning. These head and body move- activity but may occur in isolation, without loss of consciousness, ments, if they occur, are preceded by quiet staring and other au- in which case it can later be described by the patient. Postictal tomatisms. aphasia is more common and has much the same localizing value. The jacksonian motor seizure begins with a tonic contraction Vocalization at the onset of a seizure has no such significance. of the fingers of one hand, the face on one side, or the muscles of These disturbances should be distinguished from the stereotyped one foot. This transforms into clonic movements in these parts in repetition of words or phrases or the garbled speech that charac- a fashion analogous to that in a generalized clonic-tonic-clonic con- terizes some cases of complex partial seizures or the postictal con- vulsion. Sometimes a series of clonic movements of increasing fusional state. frequency build up to a tonic contraction. The movements may As pointed out by Manford and colleagues, relatively few fo- remain localized or spread (“march”) from the part first affected to cal seizures can be localized precisely from clinical data alone. other muscles on the same side of the body. In the latter, or However, when combined with scalp and intracranial EEG record- “classic,” jacksonian form, which is relatively uncommon, the sei- ing and MRI, the data are reasonably accurate. zure spreads from the hand, up the arm, to the face, and down the leg; or, if the first movement is in the foot, the seizure marches up Somatosensory, Visual, and Other the leg, down the arm, and to the face, usually in a matter of 20 to Types of Sensory Seizures 30 s. Interestingly, spontaneously occurring focal motor seizures, e.g., those beginning in the toes or fingers, may sometimes be ar- Somatosensory seizures, either focal or “marching” to other parts rested (inhibited) by applying a ligature above the affected part or, of the body on one side, are nearly always indicative of a focus in in the case of focal sensory seizures, by applying a vigorous sen- or near the postrolandic convolution of the opposite cerebral hemi- sory stimulus ahead of the advancing sensory aura. Rarely, the first sphere. Penfield and Kristiansen found the seizure focus in the post- muscular contraction is in the abdomen, thorax, or neck. In some central or precentral convolution in 49 of 55 such cases. The sen- cases, the one-sided seizure activity is followed by turning of the sory disorder is usually described as numbness, tingling, or a head and eyes to the convulsing side, occasionally to the opposite “pins-and-needles” feeling and occasionally as a sensation of side, and then by a generalized seizure with loss of consciousness. crawling (formication), electricity, or movement of the part. Pain Consciousness is not lost if the sensorimotor symptoms remain and thermal sensations may occur but are exceedingly rare. In the confined to one side. majority of cases, the onset of the sensory seizure is in the lips, Following convulsions that have a prominent focal motor sig- fingers, or toes, and the spread to adjacent parts of the body follows nature, there may be a transient paralysis of the affected limbs. a pattern determined by sensory arrangements in the postcentral This “Todd’s paralysis” persists for minutes or at times for hours (postrolandic) convolution of the parietal lobe. If the sensory symp- after the seizure, usually in proportion to the duration of the con- toms are localized to the head, the focus is in or adjacent to the vulsion. Continued focal paralysis beyond this time usually indi- lowest part of the convolution, near the sylvian fissure; if the symp- cates the presence of a focal brain lesion as the underlying cause toms are in the leg or foot, the upper part of the convolution, near of the seizure. A similar phenomenon is found in cases of focal the superior sagittal sinus or on the medial surface of the hemi- epilepsy that involve the language, somesthetic, or visual areas; sphere, is involved. here the persistent deficit corresponds to the region of brain af- Visual seizures are relatively rare but also have localizing sig- fected. nificance. Lesions in or near the striate cortex of the occipital lobe The high incidence of onset of focal motor epilepsy in the usually produce elemental visual sensations of darkness or sparks face, hands, and toes is probably related to the disproportionately and flashes of light, which may be stationary or moving and col- large cortical representation of these parts. The disease process or orless or colored. According to Gowers, red is the most frequently focus of excitation is usually in or near the rolandic (motor) cortex, reported color, followed by blue, green, and yellow. These images i.e., area 4 of Brodmann (Figs. 3-3 and 22-1); in some cases, and may be referred to the visual field on the side opposite of the lesion especially if there is a sensory accompaniment, it has been found or may appear straight ahead. If they occur on one side of the visual in the postrolandic convolution. Lesions confined to the motor cor- field, patients perceive that only one eye is affected (the one op- tex are reported to assume the form of clonic contractions, and posite the lesion), probably because most persons are aware of only short
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cap height the temporal half of a homonymous field defect. Curiously, a sei- (2) instead of a complete loss of control of thought and action, base of text zure arising in one occipital lobe may cause momentary blindness there is a period of altered behavior and consciousness, for which in both fields. It has been noted that lesions on the lateral surface the patient is later found to be amnesic. of the occipital lobe (Brodmann’s areas 18 and 19) are likely to Although it is difficult to enumerate all the psychic experi- cause a sensation of twinkling or pulsating lights. More complex ences that may occur during complex partial seizures, they may be or formed visual hallucinations are usually due to a focus in the categorized into a somewhat arbitrary hierarchy of illusions, hal- posterior part of the temporal lobe, near its junction with the oc- lucinations, dyscognitive states, and affective experiences. Sensory cipital lobe, and may be associated with auditory hallucinations. illusions, or distortions of ongoing perceptions, are the most com- The localizing value of visual auras has been confirmed recently mon. Objects or persons in the environment may shrink or recede by Bien and colleagues in a group of 20 surgically treated patients into the distance, or they may enlarge (micropsia and macropsia), with intractable seizures. They found that elementary visual hal- or perseverate as the head is moved (palinopsia). Tilting of the lucinations and visual loss were typical of occipital lobe epilepsy visual environment has been reported. Hallucinations are most of- but could also occur with seizure foci in the anteromedial temporal ten visual or auditory, consisting of formed or unformed visual and occipitotemporal regions. images, sounds, and voices; less frequently, they may be olfactory Auditory hallucinations are infrequent as an initial manifes- (usually unpleasant, unidentifiable sensations of smell), gustatory, tation of a seizure. Occasionally a patient with a focus in one su- or vertiginous. The term dyscognitive state refers to feelings of perior temporal convolution will report a buzzing or roaring in the increased reality or familiarity (de´ja` vu) or of strangeness or un- ears. A human voice, sometimes repeating unrecognizable words, familiarity (jamais vu) or a sense of depersonalization. Fragments or the sound of music, has been noted a few times with lesions in of certain old memories or scenes may insert themselves into the the more posterior part of one temporal lobe. patient’s mind and recur with striking clarity, or there may be an Vertiginous sensations of a type suggesting a vestibular origin abrupt interruption of memory. (See Gloor for a more detailed de- may on rare occasions be the first symptom of a seizure. The lesion scription of the experiential phenomena of temporal lobe epilepsy.) is usually located in the superoposterior temporal region or the Associated epigastric and abdominal sensations have been alluded junction between parietal and temporal lobes. In one of the cases to above. reported by Penfield and Jasper, a sensation of vertigo was evoked Emotional experiences, while less common, may be dra- by stimulating the cortex at the junction of the parietal and occipital matic—sadness, loneliness, anger, happiness, and sexual excite- lobes. Occasionally with a temporal focus, the vertigo is followed ment have all been recorded. Fear and anxiety are the most common by an auditory sensation. Giddiness, or light-headedness, is a fre- affective experiences, while occasionally the patient describes a quent prelude to a seizure, but this symptom, as discussed in Chap. feeling of rage or intense anger as part of a complex partial seizure. 15, has so many different connotations that it is of little diagnostic Ictal fear may have no apparent connection to objective experience value. and is generally not related to the situation in which the patient Olfactory hallucinations are often associated with disease of finds himself during the seizure. the inferior and medial parts of the temporal lobe, usually in the Each of these subjective psychic states may constitute the en- region of the parahippocampal convolution or the uncus (hence tire seizure (simple partial seizure), or some combination may oc- Jackson’s term uncinate seizures, pages 199 and 398). Usually the cur and proceed to a period of unresponsiveness. Patients call these perceived odor is exteriorized, i.e., projected to someplace in the “auras,” but they represent electrical seizures and have the same environment, and is described as disagreeable or foul, though other- significance as a motor convulsion. The motor components of the wise unidentifiable. Gustatory hallucinations have also been re- seizure, if they occur, do so during the latter phase and take the corded in proven cases of temporal lobe disease (see page 201) and form of automatisms such as lip-smacking, chewing or swallowing with lesions of the insula and parietal operculum; salivation and a movements, salivation, fumbling of the hands, or shuffling of the sensation of thirst may be associated. Electrical stimulation in the feet. Patients may walk around in a daze or act inappropriately depths of the sylvian fissure, extending into the insular region, has (undressing in public, speaking incoherently, etc.). Certain com- produced peculiar sensations of taste. plex acts that were initiated before the loss of consciousness— Vague and often indefinable visceral sensations arising in the such as walking, chewing food, turning the pages of a book, or thorax, epigastrium, and abdomen are among the most frequent of even driving—may continue. However, when asked a specific auras, as already indicated. Most often they have a temporal lobe question or given a command, the patients are obviously out of origin, although in several such cases the seizure discharge has contact with their surroundings. There may be no response at all, been localized to the upper bank of the sylvian fissure; in a few or the patient may look toward the examiner in a perplexed way others, the focus was located in the upper or middle frontal gyrus or utter a few stereotyped phrases. In a very small number of pa- or in the medial frontal area near the cingulate gyrus. Palpitation tients with temporal lobe seizures (7 of 123 patients studied by and acceleration of the pulse at the beginning of the attack have Ebner et al), some degree of responsiveness (to simple questions also been related to a temporal lobe focus. and motor commands) is preserved in the presence of prominent automatisms such as lip-smacking and swallowing. Interestingly, Complex Partial Seizures (Psychomotor in this small group of partially responsive patients, the seizures Seizures, Temporal Lobe Seizures) originate in the right temporal lobe. The patient, in a confused and irritable state, may resist or These differ from the major generalized and absence seizures dis- strike out at the examiner. The violence and aggression that are cussed above in that (1) the aura (i.e., the initial event in the seizure) said to characterize patients with temporal lobe seizures usually may be either a focal seizure of simple type or a hallucination or take this form of nondirected oppositional resistance in response perceptual illusion, indicating (usually) a temporal lobe origin, and to restraint during the period of automatic behavior (so called be- short
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cap height cause the patient presumably acts like an automaton) or, more of- led to secondary ischemic damage to the hippocampal portions of base of text ten, in the postictal period. Unprovoked assault or outbursts of the temporal lobes. In the latter cases, carefully performed and intense rage or blind fury are very unusual; Currie and associates quantitated MRI in the coronal plane may disclose a loss of volume found such outbursts in only 16 of 666 patients (2.4 percent) with in the hippocampi and adjacent gyri on one or both sides—i.e., temporal lobe epilepsy. Penfield once commented that he had never medial temporal sclerosis (Fig. 16-2). observed a rage state as a result of temporal lobe stimulation. It is Complex partial seizures are notably variable in duration. Be- exceedingly unlikely that an organized violent act requiring several havioral automatisms rarely last longer than a minute or two, al- sequential steps in its performance, such as obtaining a gun and though postictal confusion and amnesia may persist for a consid- using it, could represent a temporal lobe seizure. erably longer time. Some complex partial seizures consist only of Rarely, laughter may be the most striking feature of an au- a momentary change in facial expression and a blank spell, resem- tomatism (gelastic epilepsy). A particular combination of gelastic bling an absence. Almost always, however, the former are char- seizures and precocious puberty has been traced to a hamartoma acterized by distinct ictal and postictal phases, whereas patients of the hypothalamus. Or the patient may walk repetitively in small with absence attacks usually have an instantaneous return of full circles (volvular epilepsy), run (epilepsia procursiva), or simply consciousness following the ictus. wander aimlessly, either as an ictal or postictal phenomenon (po- Postictal behavior after partial complex seizures is often ac- riomania). These forms of seizure are actually more common with companied by widespread slowing in the EEG. With seizures of frontal lobe than with temporal lobe foci. Dystonic posturing of left-sided origin there is likely to be global and nonfluent aphasia. the arm and leg contralateral to the seizure focus is found to be a Prolonged disorientation for time and place suggests a right-sided frequent accompaniment if sought—again, the origin is more of- source. Automatisms in the postictal period have no lateralizing ten in the frontal than the temporal lobes, localizing particularly connotation (Devinsky et al). However, postictal posturing and pa- to the supplementary motor area. After the attack, the patient usu- resis of an arm (Todd’s paralysis) or an aphasic difficulty are help- ally has no memory or only fragments of recall for what was said ful in determining the side of the lesion (Cascino). Also, postictal or done. Any type of complex partial seizures may proceed to nose wiping is carried out by the hand ipsilateral to the seizure other forms of secondary generalized seizures. The tendency to focus in 97 percent of patients, according to Leutzmezer and col- generalization holds true for all types of partial or focal epilepsy. leagues, but we are in no position to confirm this. The patient with temporal lobe seizures may exhibit only one of the foregoing manifestations of seizure activity or various com- Amnesic Seizures Rarely, brief, recurrent attacks of transient binations of them. In a series of 414 patients studied by Lennox, amnesia are the only manifestations of temporal lobe epilepsy, al- 43 percent displayed some of the motor changes; 32 percent, au- though it is unclear whether the amnesia in such patients represents tomatic behavior; and 25 percent, alterations in psychic function. an ictal or postictal phenomenon. These attacks of pure amnesia Because of the frequent concurrence of these symptom com- have been referred to as transient epileptic amnesia, or TEA (Pal- plexes, he referred to them as the psychomotor triad.Probably mini et al; Zeman et al). If the patient functions at a fairly high the clinical pattern varies with the precise locality of the lesion level during the attack, as may happen, there is some resemblance and the direction and extent of spread of the electrical discharge. to transient global amnesia (page 379). However, the brevity and Because of their focal origin and complex symptomatology, all frequency of the TEA spells, their tendency to occur on awakening, these types of seizures are best subsumed under the heading of the impaired performance on complex cognitive tasks, and, of complex partial seizures.Thistermispreferabletotemporal lobe course, a history of epilepsy and associated seizure discharges in seizures,sincetypicalcomplexpartialseizuressometimesarise the EEG help to make the distinction. from a focus in the medial-orbital part of the frontal lobe. Also, seizures originating in the parietal or occipital lobes may be man- Behavioral and Psychiatric Disorders Some comments are in ifested as complex partial seizures because of seizure spread into order concerning the issues of personality, behavioral, and psy- the temporal lobes. Often the brief ictal aura is not reflected in chiatric disorders in patients with complex partial seizures. Data cortical epileptic activity and therefore may be missed by routine as to prevalence of these disorders are limited and have been de- surface EEG recordings. rived mainly from studies of selected groups of patients attending Complex partial seizures are not peculiar to any period of life, university hospitals and other specialty clinics that tend to treat the but they do show an increased incidence in adolescence and the most difficult and complicated cases. In one such study (Victoroff), adult years. In the series of Ounsted and coworkers, about one- about one-third of the patients had a history of major depressive third of such cases could be traced to the occurrence of severe illness, and an equal number had symptoms of anxiety disorder; febrile convulsions in early life (see further on). As a corollary, psychotic symptoms were found in 10 percent. Similar figures, also about 5 percent of all their patients with febrile seizures continued from a university-based epilepsy center, have been reported by Blu- to have seizures during adolescence and adult life; in the latter mer et al. It must be emphasized that these remarkable rates of group there were many in whom the seizures were of the temporal psychiatric morbidity do not reflect the prevalence in the entire lobe type. Also, in Falconer’s series in which a temporal lobectomy population of epileptics. was performed for intractable epilepsy, there were many patients The postictal state in patients with temporal lobe epilepsy who had previously had this complicated type of febrile seizure. sometimes takes the form of a protracted paranoid-delusional or Neonatal convulsions, head trauma, and various other nonprogres- amnesic psychosis lasting for days or weeks. The EEG during this sive perinatal neurologic disorders are antecedents that place a child period may show no seizure discharge, though this does not exclude at risk of developing complex partial seizures (Rocca et al). Two- repeated or sustained seizure activity in the amygdala and other thirds of patients with complex partial seizures also have general- deep temporal lobe structures. This disorder, virtually indistin- ized tonic-clonic seizures or have had them at some earlier time, guishable from schizophrenia in form (but not in temporal evolu- short and it has been theorized that the generalized seizures may have tion), may also present in the interictal period. An excess of psy- stand
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AB Figure 16-2. Medial temporal sclerosis. A. Thin-slice volumetric MRI in the coronal plane, showing shrinkage of the right hippocampus (shown by arrow) and secondary enlargement of the temporal horn of the lateral ventricle. B. T2-weighted image showing signal change in the hippocampi (shown by arrow). (Courtesy of Dr. Peter Williamson.) chosis has been reported only in studies emanating from specialized would distinguish patients with temporal lobe epilepsy from other centers; epidemiologic studies provide only limited evidence of an groups of epileptics. The problem of personality disturbances in association with psychosis in the overall population of epileptics epilepsy remains to be clarified (see review by Trimble). (see Trimble and Schmitz and the review by Trimble for a critical discussion of this subject). Again, the frequency of this association SPECIAL EPILEPTIC SYNDROMES with temporal lobe epilepsy is uncertain. There remain to be considered several epileptic syndromes and Epileptic Personality Disorder It has long been observed that other seizure states that cannot be readily classified with the usual some patients with temporal lobe seizures may exhibit a number types of generalized or partial seizures. These special types are of abnormalities of behavior and personality during the interictal described below. period. Often they are slow and rigid in their thinking, verbose, circumstantial and tedious in conversation, inclined to mysticism, Benign Childhood Epilepsy with and preoccupied with rather naive religious and philosophical Centrotemporal Spikes (Rolandic ideas. Also, they are often subject to outbursts of bad temper and Epilepsy, Sylvian Epilepsy) and aggressiveness. Obsessionalism, humorless sobriety, emotionality Epilepsy with Occipital Spikes (mood swings, sadness and anger), and a tendency to paranoia are other frequently described traits. Diminished sexual interest and This type of focal motor epilepsy is unique among the partial ep- potency in men and menstrual problems in women, not readily ilepsies of childhood in that it tends to be a self-limited disorder, attributable to anticonvulsant drugs, are common among patients transmitted in families as an autosomal dominant trait. The con- with complex partial seizures of temporal lobe origin. Geschwind vulsive disorder begins between 5 and 9 years of age and usually proposed that a triad of behavioral abnormalities—hyposexuality, announces itself by a nocturnal tonic-clonic seizure with focal on- hypergraphia, and hyperreligiosity—constitute a characteristic set. Thereafter, the seizures take the form of clonic contractions of syndrome in such patients. one side of the face, less often of one arm or leg, and the interictal Bear and Fedio have suggested that certain of these traits (ob- EEG shows high-voltage spikes in the contralateral lower rolandic sessionalism, elation, sadness, and emotionality) are more common or centrotemporal area. The seizures are readily controlled by a with right temporal lesions and that anger, paranoia, and cosmo- single anticonvulsant drug and gradually disappear during adoles- logic or religious conceptualizing are more characteristic of left cence. The relation of this syndrome to acquired aphasia with con- temporal lesions. However, Rodin and Schmaltz, who administered vulsive disorder in children, described by Landau and Kleffner, is the Bear-Fedio inventory to patients with both primary generalized unsettled. and temporal lobe epilepsy, found no features that would distin- A similar type of epilepsy, usually benign in the sense that guish patients with right-sided temporal foci from those with left- there is no intellectual deterioration and a cessation of seizures in short sided ones. Moreoever, they found no behavioral changes that adolescence, has been associated with spike activity over the oc- stand
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cap height cipital lobes, as identified by Panayiotopoulos. As described in the the same or different illnesses (complicated febrile seizures). These base of text review by Taylor and colleagues, visual hallucinations, while not seizures may recur not only with infections but also at other times. invariable, are the most common clinical feature; sensations of When patients with both types are lumped together under the rubric movements of the eyes, tinnitus, or vertigo are also reported in of febrile convulsions, it is not surprising that a high percentage cases of occipital epilepsy. These authors point out symptomatic are complicated by atypical petit mal, atonic, and astatic spells causes of the syndrome, such as cortical heterotopias. In both of followed by tonic seizures, mental retardation, and partial complex these types of childhood epilepsy, the observation that spikes are epilepsy. Falconer, who studied psychomotor seizures in adults, greatly accentuated by sleep is a useful diagnostic aid. noted retrospectively a high incidence of “febrile seizures” during the infancy and childhood in his cohort of surgical subjects. The Infantile Spasms (West Syndrome) present authors believe that he was referring to complicated febrile seizures, i.e., fever and convulsions with structural brain disease, This is the term applied to a particular form of epilepsy of infancy which should be kept separate from the common benign febrile and early childhood. West, in the mid-nineteenth century, described seizures. In a later study of 67 patients with proven medial temporal the condition in his son in exquisite detail. This seizure disorder, lobe epilepsy (French et al), 70 percent had a history of complicated which in most cases appears during the first year of life, is char- febrile seizures during the first 5 years of life, although many did acterized by recurrent, single or brief episodes of gross flexion not develop temporal lobe epilepsy until their teens. Bacterial men- movements of the trunk and limbs and, less frequently, by exten- ingitis was another important risk factor; head and birth trauma sion movements (hence the alternative terms infantile spasms or were less common factors. All of the patients had complex partial salaam or jackknife seizures). Most but not all patients with this seizures and half of them, in addition, had secondarily generalized disorder show severe EEG abnormalities, consisting of continuous tonic-clonic seizures. multifocal spikes and slow waves of large amplitude. However, Epidemiologic studies have substantiated this clinical point of this pattern, referred to originally by Gibbs and Gibbs as hypsar- view. Annegers and colleagues observed a cohort of 687 children rhythmia (“mountainous” dysrhythmia), is not specific for infantile for an average of 18 years after their initial febrile convulsion. spasms, being frequently associated with other developmental or Overall, these children had a fivefold excess of unprovoked sei- acquired abnormalities of the brain. As the child matures, the sei- zures in later life. Among the children with simple febrile convul- zures diminish; they usually disappear by the fourth to fifth year. sions, the risk was only 2.4 percent. By contrast, children with what If MRI and computed tomography (CT) scans are more or less Annegers et al called complex febrile convulsions (focal, pro- normal, the usual pathologic findings according to Jellinger are longed, or repeated episodes of febrile seizures) had a greatly in- cortical dysgeneses. Both the seizures and the EEG abnormalities creased risk—8, 17, or 49 percent, depending on the association may respond dramatically to treatment with adrenocorticotropic of one, two, or three of the complicating features. hormone (ACTH), corticosteroids, or the benzodiazepine drugs, of which clonazepam is probably the most widely used. However, Reflex Epilepsy most patients, even those who were apparently normal when the seizures appeared, are left mentally impaired. Infantile spasms may For a long time it has been known that seizures could be evoked also be part of the Lennox-Gastaut syndrome, a seizure disorder of in certain epileptic individuals by a discrete physiologic or psy- early childhood of grave prognosis (see page 274). chologic stimulus. The term reflex epilepsy is reserved for this small subgroup. Forster has classified these seizures in accordance Febrile Seizures with their evocative stimuli into five types: (1) visual—flickering light, visual patterns, and specific colors (especially red), leading The well-known febrile seizure, peculiar to infants and children to rapid blinking or eye closure; (2) auditory—sudden unexpected between 6 months and 5 years of age (peak incidence 9 to 20 noise (startle), specific sounds, musical themes, and voices; (3) months) and with a strong tendency to be inherited, is generally somatosensory—either a brisk unexpected tap or sudden move- regarded as a benign condition. Usually it takes the form of a single, ment after sitting or lying still, or a prolonged tactile or thermal generalized motor seizure occurring as the temperature rises or stimulus to a certain part of the body; (4) writing or reading of reaches its peak. Seldom does the seizure last longer than a few words or numbers; and (5) eating. minutes; by the time an EEG can be obtained, there is usually no Visually induced seizures are by far the most common type abnormality. Recovery is complete. Except for a presumed genetic of reflex epilepsy. The seizures are generalized and are most often relationship with benign epilepsy of childhood (Luders et al), triggered by the photic stimulation of television or an EEG ex- which in itself is transient in nature, these patients’ risk of devel- amination or by the photic or pattern stimulation of video games. oping epilepsy in later life is only slightly greater than that of the In other types of reflex epilepsy, the evoked seizure may be focal general population. In some families, such as those studied by Nab- (beginning often in the part of the body that was stimulated) or bout and colleagues, febrile seizures alone, without generalized ep- generalized and may take the form of one or a series of myoclonic ilepsy, have been associated with a particular gene defect by link- jerks or of an absence or tonic-clonic seizure. Seizures induced by age analysis. Presumably, when the gene product is identified, reading, voices, or eating are most often of the complex partial some insight into the nature of defects that lower the seizure thresh- type; seizures induced by music are usually myoclonic. A few such old will be forthcoming. instances of reflex epilepsy have been due to focal cerebral disease, This benign type of febrile seizure should not be confused particularly occipital lesions. with a second and more serious type of illness in which an acute Clonazepam, valproate, carbamazepine, and phenytoin are all encephalitic or encephalopathic state presents during a febrile ill- effective in controlling individual instances of reflex epilepsy. ness with focal or prolonged seizures, generalized or focal EEG Some patients learn to avert the seizure by undertaking a mental short abnormalities, and repeated episodes of febrile convulsions with task, e.g., thinking about some distracting subject, counting, etc., stand
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cap height or by initiating some type of physical activity. Forster has dem- Hysterical Seizures base of text onstrated that in certain types of reflex epilepsy, the repeated pre- sentation of the noxious stimulus may eventually render the stim- These episodes, referred to as “psychogenic” seizures, are non- ulus innocuous. This technique requires a great deal of time and epileptic in nature—i.e., they are not caused by an abnormal neu- assiduous reinforcement, which limits its therapeutic value. ronal discharge. They are mentioned here because they are quite common and frequently mistaken for epileptic seizures and treated Epilepsia Partialis Continua with anticonvulsant drugs, to which they are characteristically un- responsive. Such seizures are most often a symptom of hysteria in This is another special type of focal motor epilepsy characterized the female (Briquet disease) or of compensation neurosis and ma- by persistent rhythmic clonic movements of one muscle group— lingering in males and females, in which case the terms sham sei- usually of the face, arm, or leg—which are repeated at fairly reg- zures and pseudoseizures are appropriate. Of course, patients with ular intervals every few seconds and continue for hours, days, true epileptic seizures sometimes exhibit hysterical seizures as well, weeks, or months without spreading to other parts of the body. and distinguishing the two may be difficult. Usually, however, the Thus epilepsia partialis continua is, in effect, a highly restricted motor display in the course of a nonepileptic seizure is sufficient and very persistent focal motor status epilepticus. The distal mus- to identify it as such: completely asynchronous thrashing of the cles of the leg and arm, especially the flexors of the hand and limbs and repeated side-to-side movements of the head; striking fingers, are affected more frequently than the proximal ones. In the out at a person who is trying to restrain the patient; hand-biting, face, the recurrent contractions involve either the corner of the kicking, trembling, and quivering; pelvic thrusting and opistho- mouth or one or both eyelids. Occasionally, isolated muscles of the tonic arching postures; and screaming or talking during the ictus. neck or trunk are affected on one side. The clonic spasms may In general, pseudoseizures tend to occur in the presence of other be accentuated by active or passive movement of the involved people, to be precipitated by emotional factors, and to be prolonged muscles and may be reduced in severity but not abolished during for many minutes or hours; with few exceptions, tongue-biting, sleep. incontinence, hurtful falls, or postictal confusion are lacking. No First described by Kozhevnikov in patients with Russian single one of these features is determinative, however. spring-summer encephalitis, these partial seizures may be induced Prolonged fugue states in our practice usually have proved to by a variety of acute or chronic cerebral lesions. In some cases the be manifestations of hysteria or a psychopathy even in a known underlying disease is not apparent (this applies to about half of our epileptic. The serum creatine kinase and prolactin levels are normal cases), and the clonic movements may be mistaken for some type after hysterical seizures; this may be helpful in distinguishing them of slow tremor or extrapyramidal movement disorder. Most pa- from genuine convulsions. Where doubt remains, a recording of tients with epilepsia partialis continua show focal EEG abnormal- the ictal or postictal EEG or the combined video and EEG recording ities, either repetitive slow-wave abnormalities or sharp waves or of an attack will settle the issue. This subject is discussed further spikes over the central areas of the contralateral hemisphere. In in Chap. 56. some cases, the spike activity can be related precisely in location and time to the clonic movements (Thomas et al). In the series of THE NATURE OF THE cases collected by Obeso and colleagues, there were various com- DISCHARGING LESION binations of epilepsia partialis continua and cutaneous reflex my- oclonus (cortical mycolonus occurring only in response to a variety Physiologically, the epileptic seizure has been defined as a sudden of afferent stimuli); these investigators view epilepsia partialis con- alteration of central nervous system (CNS) function resulting from tinua as part of a spectrum of motor disorders that also includes a paroxysmal high-frequency or synchronous low-frequency, high- stimulus-sensitive myoclonus, focal motor seizures, and grand mal voltage electrical discharge. This discharge arises from an assem- seizures. blage of excitable neurons in any part of the cerebral cortex and As would be expected, a wide range of causative lesions has possibly in secondarily involved subcortical structures as well. Of been implicated—developmental anomalies, encephalitis, demye- course, there need not be a visible lesion. In the proper circum- linative diseases, brain tumors, and degenerative diseases; but in stances, a seizure discharge can be initiated in an entirely normal many instances, as mentioned, the underlying cause is not found cerebral cortex, as when the cortex is activated by ingestion or even after extensive investigation. Epilepsia partialis continua has injection of drugs, by withdrawal from alcohol or other sedative been particularly common in patients with Rasmussen encephalitis drugs, or by repeated stimulation with subconvulsive electrical (page 289). As a rule, this type of seizure activity responds poorly pulses (“kindling phenomenon”). or not at all to anticonvulsant medications, but there is little alter- Viewed from a larger physiologic perspective, seizures require native other than to try several drugs in combination. Surgical ex- three conditions: (1) a population of pathologically excitable neu- tirpation or circumscription of the discharging cortex is a last resort. rons; (2) an increase in excitatory glutaminergic activity through Whether cortical mechanisms or subcortical ones are respon- recurrent connections in order to spread the discharge; and (3) a sible for epilepsia partialis continua is an unresolved question. The reduction in the activity of the normally inhibitory GABA-nergic electrophysiologic evidence adduced by Thomas and colleagues projections. The last of these has been challenged, but it is sup- favors a cortical origin. The pathologic evidence is less definite. In ported by considerable data and serves as a reasonable model, as each of eight cases in which the brain was examined postmortem, noted below. Understanding of the initial discharges and their they found some degree of involvement of the motor cortex or spread has been greatly advanced by the identification of several adjacent cortical area contralateral to the affected limbs. However, rare forms of familial epilepsy that are the direct result of mutations all but one of these patients also had some involvement of deeper in sodium, potassium, acetylcholine receptor, or GABA channels structures on the same side as the cortical lesion, on the opposite on neurons. These are discussed further under “Genetics of Epi- short side, or on both sides. lepsy.” stand
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cap height Just why the neurons in or near a focal cortical lesion dis- et al). This suggests that seizures are triggered either by a change base of text charge abnormally is not fully understood. Some of the electrical in central thalamic rhythm generators or a subtle change in the properties of a cortical epileptogenic focus suggest that its neurons electrical activity in the region of a focal lesion. The clinical util- have been deafferented. Such neurons are known to be hyperex- ity of this finding has not been determined. Even more provoca- citable, and they may remain so chronically, in a state of partial tive are the findings of Litt and colleagues; using complex tech- depolarization, able to fire irregularly at rates as high as 700 to niques in a small number of patients, they have detected 1000 per second. The cytoplasmic membranes of such cells appear prolonged bursts of seizure-like activity days before the onset of to have an increased ionic permeability, which renders them sus- temporal lobe seizures. Their unconventional proposal is that ceptible to activation by hyperthermia, hypoxia, hypoglycemia, hy- these events cause a cascade of electrophysiologic changes that pocalcemia, and hyponatremia as well as by repeated sensory (e.g., very gradually culminate in a seizure. photic) stimulation and during certain phases of sleep (where hy- If unchecked, cortical excitation spreads to the adjacent cortex persynchrony of neurons is known to occur). and to the contralateral cortex via interhemispheric pathways and As an example, epileptic foci induced in the animal cortex by also to anatomically and functionally related pathways in subcor- the application of penicillin are characterized by spontaneous in- tical nuclei (particularly the basal ganglionic, thalamic, and brain- terictal discharges, during which the neurons of the discharging stem reticular nuclei). It is at this time that the clinical manifesta- focus exhibit large, presumably Ca-mediated paroxysmal depolar- tions of the seizure begin, the initial signs and symptoms depending izing shifts (PDSs), followed by prolonged after-hyperpolarizations on the portion of the brain from which the seizure originates. The (AHPs). The latter also are due in part to Ca-dependent K currents excitatory activity from the subcortical nuclei is fed back to the but are better explained by enhanced synaptic inhibition. The PDSs original focus and to the other parts of the forebrain, a mechanism occur synchronously in the penicillin focus and summate to pro- that serves to amplify their excitatory activity and to give rise to duce surface-recorded interictal EEG spikes; the AHPs correspond the characteristic high-voltage polyspike discharge in the EEG. to the slow wave of the EEG spike-and-wave complex (Engel). The There is propagation downward to spinal neurons as well, via cor- neurons surrounding the epileptogenic focus are hyperpolarized ticospinal and reticulospinal pathways, yielding a generalized from the beginning and are inhibitory and release gamma amino- tonic-clonic convulsion. butyric acid. Seizure spread probably depends on any factor or The spread of excitation to the subcortical, thalamic, and agent that activates neurons in the focus or inhibits those surround- brainstem centers is thought to correspond to the tonic phase of ing it. The precise mechanisms that govern the transition from a the seizure and loss of consciousness as well as to the signs of circumscribed interictal discharge to a widespread seizure state are autonomic nervous system overactivity (salivation, mydriasis, not understood. tachycardia, increase in blood pressure). Vital functions may be Biochemical studies of neurons from a seizure focus have not arrested, but usually for only a few seconds. In rare instances, greatly clarified the problem. Levels of extracellular K are found however, death may occur owing to a sustained cessation of res- to be elevated in glial scars near epileptic foci, and a defect in piration, a derangement of cardiac action, or some unknown voltage-sensitive Ca channels has also been postulated. Epileptic cause. The development of unconsciousness and the generalized foci are known to be sensitive to acetylcholine and to be slower in tonic contraction of muscles is reflected in the EEG by a diffuse binding and removing it than is normal cerebral cortex. A defi- high-voltage discharge pattern appearing simultaneously over the ciency of the inhibitory neurotransmitter GABA, increased glycine, entire cortex. decreased taurine, and either decreased or increased glutamic acid Soon after the spread of excitation, a diencephalocortical in- have been variously reported in excised human epileptogenic tis- hibition begins and intermittently interrupts the seizure discharge, sue, but whether these changes are the cause or result of seizure changing it from the persistent discharge of the tonic phase to the activity has not been determined. The interpretation of reported intermittent bursts of the clonic phase. Electrically, a transition oc- abnormalities of GABA, biogenic amines, and acetylcholine in the curs from a continuous polyspike to a spike-and-wave pattern. The cerebrospinal fluid (CSF) of epileptic patients poses similar diffi- intermittent clonic bursts become less and less frequent and finally culties. cease altogether, leaving in their wake an “exhaustion” (paralysis) Concurrent EEG recordings from an epileptogenic cortical of the neurons of the epileptogenic focus and a regional increase focus and subcortical, thalamic, and brainstem centers in the an- in permeability of the blood-brain barrier. An overshoot of these imal model have enabled investigators to construct a sequence of inhibitory mechanisms is thought to be the basis of Todd’s post- electrical and clinical events that characterize an evolving focal epileptic paralysis (and of postictal stupor, sensory loss, aphasia, seizure. Firing of the involved neurons in the cortical focus is hemianopia, headache, and diffuse slow waves in the EEG, as de- reflected in the EEG as a series of periodic spike discharges, scribed earlier) and regional edema in T2-weighted MR images. which increase progressively in amplitude and frequency. Once Plum and associates have observed a two- to threefold increase in the intensity of the seizure discharge exceeds a certain point, it glucose utilization during seizure discharges and suggested that the overcomes the inhibitory influence of surrounding neurons and paralysis that follows might be due to neuronal depletion of glucose spreads to neighboring cortical regions via short corticocortical and increase in lactic acid. However, inhibition of epileptogenic synaptic connections. If the abnormal discharge remains confined neurons may occur in the absence of neuronal exhaustion. The to the cortical focus and the immediate surrounding cortex, there exact roles played by each of these factors in postictal paralysis of are probably no clinical symptoms or signs of seizure, and the function are not settled. EEG abnormality that persists during the interseizure period re- Bilaterally synchronous three-per-second high-voltage spike- flects this restricted type of abnormal cortical activity. A provoc- and-wave discharges and seizures resembling absence attacks have ative new finding, based on sophisticated mathematical analysis been produced in animals by a number of experimental procedures. of EEG tracings, demonstrates subtle electrographic changes up The spike-and-wave complex, which represents brief excitation fol- short to several minutes before the ictal discharge (see LeVan Quyen lowed by slow-wave inhibition, is the type of EEG pattern that stand
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cap height characterizes the clonic (inhibitory) phase of the focal motor or The Electroencephalogram in Epilepsy base of text grand mal seizure. By contrast, this strong element of inhibition is (See also Chap. 2.) present diffusely throughout an “absence” attack, a feature that per- haps accounts for the failure of excitation to spread to lower brain- The EEG provides confirmation of Hughlings Jackson’s concept of stem and spinal structures (tonic-clonic movements do not occur). epilepsy—that it represents a recurrent, sudden, excessive dis- However, the absence seizure can also at times activate the mech- charge of cortical neurons. The EEG is undoubtedly the most sen- anism for rhythmic myoclonus, probably at an upper brainstem sitive, indeed indispensable, tool for the diagnosis of epilepsy; but level. like other ancillary tests, it must be used in conjunction with clin- Current physiologic data indicate that the characteristic EEG ical data. In patients with idiopathic generalized seizures and in a patterns of both generalized forms of epilepsy (i.e., tonic or tonic- high proportion of their relatives, interictal spike-and-wave abnor- clonic and absence) are generated in the neocortex and are en- malities without any clinical seizure activity are common, espe- hanced by the synchronizing influences of subcortical structures. cially if the EEG is repeated several times. Contrariwise, a pro- In both instances, the generalization of the clinical and electrical portion of epileptic patients have a perfectly normal interictal EEG; manifestations depends upon activation of a deep, centrally lo- occasionally, using standard methods of scalp recording, the EEG cated physiologic mechanism, which, for reasons outlined in may even be normal during a simple or complex partial seizure. Chap. 17, includes the midbrain reticular formation and its dien- Furthermore, a small number of healthy persons (approximately 2 cephalic extension, the intralaminar and nonspecific thalamic pro- to 3 percent) show paroxysmal EEG abnormalities; some of them jection systems (originally referred to by Penfield as the “cen- have a family history of epilepsy (particularly of absence seizures) trencephalon”). There is no evidence, however, that seizure and may themselves later develop seizures. activity originates in these deep activating structures; therefore EEG abnormalities that characterize a spreading epileptogenic the term centrencephalic epilepsy has been replaced by corticor- focus and generalization of seizure activity, both the grand mal and eticular epilepsy. absence types, have been described in the preceding section and Complex partial seizures are almost always of temporal lobe are illustrated in Chap. 2. At first there was thought to be a char- origin, arising in foci in the medial temporal lobe, amygdaloid nu- acteristic EEG picture for seizures, but further studies have not clei, and hippocampus. Only rarely do they originate in the con- confirmed this, many patterns being possible. One consistent ob- vexity of the temporal lobe and propagate to the amygdaloid nuclei, servation, however, has been that the region of earliest spike activ- hippocampus, and posteroinferior parts of the frontal lobe. Electri- ity corresponds best to the epileptogenic focus. This rule guides cal stimulation in these areas reproduces feelings of depersonali- epilepsy surgery. The postseizure or postictal state following gen- zation, emotionality, and automatic behavior, the characteristic fea- eralized seizures also has its EEG correlate, taking the form of tures of psychomotor epilepsy. The automatic behavior appears to random generalized slow waves. Following partial or focal sei- be a direct effect of the temporal lobe discharge in some instances zures, the EEG shows focal slowing. With clinical recovery, the and a postexcitatory or inhibitory effect in others. Loss of memory EEG returns to normal or to the preseizure state. A single EEG for the events of the episode may be due to the paralytic effect of tracing obtained during the interictal state is abnormal to some the discharge on neurons of the hippocampus. degree in 30 to 50 percent of epileptic patients; this figure rises to Of theoretical importance is the observation that a seizure fo- 60 to 70 percent if patients are subjected to three or more studies cus, if active for a time, may sometimes establish, via commissural utilizing standard activating measures (hyperventilation, photic connections, a persistent secondary focus in the corresponding cor- stimulation, and sleep; see Chap. 2). With structural lesions, focal tical area of the opposite hemisphere (mirror focus). The nature of slow and sharp activity, which is not clearly epileptiform, may be this phenomenon is obscure; it may be similar to the “kindling” the only clue to a seizure focus. phenomenon mentioned earlier in animals, where a repeated non- A higher yield of abnormalities and a more precise definition convulsive electrical stimulation of normal cortex induces a per- of seizure types can be obtained by the use of several special EEG manent epileptic focus. No morphologic change is visible in the procedures. Overnight EEG recording is particularly helpful be- mirror focus, at least by light microscopy. The mirror focus may cause focal abnormalities, particularly in the temporal lobes, may be a source of confusion in trying to identify the side of the primary become prominent in stage II sleep. Sphenoidal leads have been lesion by EEG, but there is little evidence that it can produce used to detect inferomedial temporal seizure activity, but they are chronic seizures in humans. Similarly, there are no firm data sup- uncomfortable and probably add little more information than can porting a role for kindling in the diagnosis and management of be obtained by the placement of additional subtemporal scalp elec- patients with epilepsy (Goldensohn). trodes. In our experience, nasopharyngeal electrode recordings are Severe seizures may be accompanied by a systemic lactic ac- too contaminated by artifact to be clinically useful. Activating pro- idosis with a fall in arterial pH, reduction in arterial oxygen satu- cedures such as hyperventilation, photic stroboscopic stimula- ration, and rise in PCO2. These effects are secondary to the respi- tion, and sleep increase the yield of EEG recordings, as detailed in ratory arrest and excessive muscular activity. If prolonged, they Chap. 2. may cause hypoxic-ischemic damage to remote areas in the cere- Beyond dependably identifying artifacts in the EEG recording, brum, basal ganglia, and cerebellum. In paralyzed and artificially one of the main challenges for the electroencephalographer is to ventilated subjects receiving electroconvulsive therapy, these differentiate between normal patterns that simulate seizures and changes are less marked and the oxygen tension in cerebral venous true epileptic discharges. These paroxysmal but ostensibly normal blood may actually rise. Heart rate, blood pressure, and particularly patterns appear mostly during sleep, each with a highly character- CSF pressure rise briskly during the seizure. According to Plum istic morphology. These include small sharp spikes, “14 and 6” and colleagues, the rise in blood pressure evoked by the seizure polyspike activity, lambda and posterior occipital mu rhythm, and usually causes a sufficient increase in cerebral blood flow to meet occipital sharp transients. These are pictured in most standard text- short the increased metabolic needs of the brain. books on the subject of EEG. stand
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cap height Several methods of long-term EEG monitoring are now in thalamic hormones, rise for 10 to 20 min after all types of gener- base of text common use and are of particular value in the investigation of alized seizures, including complex partial seizures, but not in ab- patients with surgically removable epileptogenic foci. The most sence or myoclonic types. An elevation may help differentiate a common of these makes use of telemetry systems, in which the hysterical seizure from a genuine one; however, serum prolactin patient is attached to the EEG machine by cable or radio transmitter may also be slightly elevated after a syncopal episode. Detection without unduly limiting his freedom of movement. The telemetry is facilitated by collecting capillary blood from the finger on filter system is joined to an audiovisual recording system, making it paper for analysis (Fisher et al). There is also a postictal rise in possible to record seizure phenomena (even at night, under dim ACTH and serum cortisol, but these changes have a longer latency infrared light) and to synchronize them with the EEG abnormali- and briefer duration. If changes in these hormonal levels are used ties. An alternative is the use of a small cassette recorder that is as diagnostic tests, one must have information about normal base- attached to a miniature EEG machine worn by the patient at home line levels, diurnal variations, and the effects of concurrent medi- and at work. The patient is instructed to push a button if he expe- cations. Changes in body temperature, which are said to sometimes riences an “event,” which can later be correlated with EEG activity. precede a seizure, may reflect hypothalamic changes but are far The role of intensive neurodiagnostic monitoring in the investiga- less consistent and difficult to use in clinical work. tion and treatment of seizures, which is also a necessary part of the evaluation for epilepsy surgery, is described in detail in the mon- Pathology of Epilepsy ographs of Engel and of Niedermeyer. The EEG changes in epilepsy are discussed further in In most autopsied cases of primary generalized epilepsy of the Chap. 2. grand mal and absence types, the CNS has been said to be grossly and microscopically normal. However, it is unlikely that the brains Other Laboratory Abnormalities in these cases were examined completely—at least there is not a Associated with Seizures single case that has been subjected to whole-brain serial sectioning in a search for disorders of neural migration and old scars. Not MRI is the most important diagnostic tool for the detection of struc- surprisingly, there are also no visible lesions in the seizure states tural abnormalities underlying epilepsy. Medial temporal sclerosis, complicating drug intoxication and withdrawal, transient hyper- glial scars, porencephaly, heterotopias, and other disorders of neu- and hyponatremia, and hyper- and hypoglycemia, which presum- ronal migration can be clearly visualized. After a seizure, particu- ably represent derangements at the cellular level. larly one with a focal component, MRI sometimes discloses subtle In contrast, most of the so-called secondary epilepsies have focal cortical swelling and signal change in the FLAIR sequence, definable lesions. These include zones of neuronal loss and gliosis or, if a contrast agent is administered, an ill-defined cortical blush (scars) or other signs of tissue loss such as a porencephaly, heter- may be visible on CT or MRI. There is a rough relationship be- otopia, dysgenetic cortex, hamartoma, vascular malformation, and tween the duration of seizure activity and the intensity and size of tumor. The frequency of these lesions is not fully known. Certainly these cortical changes. Likewise, angiography performed soon after the focal epilepsies are associated with the highest incidence of a seizure may show a focal area of enhanced flow. This phenom- structural abnormalities, although in certain cases no morphologic enon was often a source of confusion when radionuclide scans were change is visible. In several series of cases of temporal lobe exci- routinely performed for the evaluation of new seizures—focal in- sions, such as that of Falconer, a specific pattern of neuronal loss creased uptake being mistaken for a tumor or stroke. All of these with gliosis (sclerosis) in the hippocampal and amygdaloid region imaging abnormalities are thought to reflect transient disruption of was found in the majority, and this abnormality is being increas- the blood-brain barrier, and they rarely persist for more than a day ingly recognized with MRI, as noted below. Vascular malforma- or two. Less well understood is the finding on MRI of increased tions, hamartomas, and low-grade astrocytomas were less frequent; T2 signal (probably due to hypoxia) in the hippocampi after a pro- in a small number, no abnormalities could be found. longed seizure or status epilepticus. The widespread use of CT and MRI represents an important The CSF occasionally contains a small number of white blood surrogate approach to the pathologic study of epilepsy. More than cells (rarely up to 50/mm3, but more often in the range of 10/mm3) 25 years ago, Gastaut and Gastaut reported that in primary grand in about 15 percent of patients after a seizure. A slight increase in mal and absence epilepsies, CT abnormalities were found in ap- protein is also possible. Like the imaging abnormalities these find- proximately 10 percent of cases, whereas in the Lennox-Gastaut ings may lead to spurious conclusions about the presence of an syndrome, the West syndrome, and partial complex epilepsies it intracranial infection, particularly if polymorphonuclear leukocytes was found in 52, 77, and 63 percent, respectively. Atrophy, calci- predominate. Nonetheless, a significant pleocytosis after a seizure fication, and malformations were the most frequent changes. MRI should always be construed as a sign of inflammatory or infectious and particularly the FLAIR images have proved to be a particularly disease. sensitive means of detecting epileptogenic lesions of the medial- Systemic acidosis is a common result of convulsive seizures, basal portion of the temporal lobes (mesial temporal sclerosis; Fig. and it is not unusual for the serum pH to reach levels near or below 16-2). Repeatedly, patients are observed in whom MRI disclosed 7 if taken immediately after a convulsion. Of more practical value a cortical or subcortical developmental malformation such as a cor- is the fact that almost all generalized convulsions produce a rise in tical heterotopia or another surgically treatable lesion of the tem- serum creatine kinase activity that persists for hours, a finding that poral lobe, even after CT scanning had failed to do so. More subtle could be used to greater advantage in emergency departments to epileptogenic foci may be demonstrated by positron emission to- assist in distinguishing seizures from fainting. Of course, extensive mography (PET) or by interictal single-photon emission computed muscle injury from a fall or prolonged compression during a period tomography (SPECT). Ictal SPECT, which shows hyperperfusion of unconsciousness can produce the same abnormality. of the seizure focus, is a more demanding but also more sensitive short
Concentrations of serum prolactin, like those of other hypo- and specific procedure. stand
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cap height With reference to the focal epilepsies, it has not been possible units of the nicotinic acetylcholine receptor subunit); generalized base of text to determine which component of the lesion is responsible for the epilepsy with febrile seizures (subunits of a neuronal sodium chan- seizures. Gliosis, fibrosis, vascularization, and meningocerebral nel); benign familial neonatal convulsions (two different potassium cicatrix have all been incriminated, but they are found in nonepi- channels); and forms of juvenile myoclonic epilepsy and childhood leptic foci as well. The Scheibels’ Golgi studies of neurons from absence epilepsy (subunits of the brain GABAA receptor). These epileptic foci in the temporal lobe showed distortions of dendrites, are summarized in Table 16-3 and their number will almost cer- loss of dendritic spines, and disorientation of neurons near the tainly expand in the next few years. As with numerous other genetic scars, but these findings have dubious status since they were not neurologic disorders, a single mutation may produce different sei- usually compared with similar nonepileptic lesions. Moreover, zure types, and a single type may be the result of one of several changes such as these have proved to be nonspecific and artifactual. different mutations. This is particularly true in a group that has Once a gliotic focus of whatever cause, bordered by groups of been termed generalized epilepsy with febrile seizures plus. This discharging neurons, becomes epileptogenic, it may remain so denotes various combinations of uncomplicated febrile seizures, throughout the patient’s lifetime. Nevertheless, with the passage of febrile seizures persisting beyond childhood, generalized, absence, years, seizures tend to diminish or cease in as many as half of myoclonic, atonic, and temporal lobe seizures. Several of the mu- childhood and adult traumatic epilepsies. tations mentioned above, two in sodium channels and one in a The most common histologic finding in the brains of epileptics GABA receptor subunit, produce this constellation, the manifes- is a bilateral loss of neurons in the CA1 segment (Sommer sector) tations of any one of these mutations varying between members of of the pyramidal cell layer of the hippocampus, extending into con- a single family. Also notable is the low penetrance of some mon- tiguous regions of both the pyramidal layer and the underlying ogenic epileptic disorders, particularly the autosomal dominant one dentate gyrus. It is still undecided whether this neuronal loss is associated with nocturnal frontal seizures. primary or secondary and, if the latter, whether it was incurred at Another group of epilepsies with mendelian inheritance has birth or happened later as the consequence of recurrent seizures. been ascribed to genetic defects that do not implicate ion channels. The cessation of seizures in many patients following surgical re- Most of these are primarily myoclonic disorders in which the ep- section of the medial temporal lobe favors the first interpretation ilepsy is symptomatic. Thus, two forms of progressive myoclonic (page 298). Attesting to the uncertainty of cause or effect regard- epilepsy, Unverricht-Lundborg disease and Lafora body disease, ing hippocampal damage are case reports and surgical series too are the result respectively of mutations in genes encoding cystatin numerous to list that favor one view or the other. It can be stated, B and a protein, tyrosine phosphatase. Other forms of myoclonic however, that seizures, even in adulthood, are capable of inducing epilepsy are presumably related to primary defects that cause dif- hippocampal shrinkage. This does not preclude a causative role for ferent forms of ceroid lipofuscinosis (see Chap. 37). To these in- medial temporal sclerosis (see editorial by Sutula and Pitka¨nen). herited forms of epilepsy may be added diseases such as tuberous sclerosis, which have a strong proclivity to cause seizures. Role of Heredity A more complex genetic element is also identified in several other classic childhood seizure disorders—absence epilepsy with Most primary epilepsies are thought to have a genetic basis and, three-per-second spike-and-wave discharges and benign epilepsy as in many other idiopathic diseases such as diabetes and athero- of childhood with centrotemporal spikes—both of which are trans- sclerosis, the mode of inheritance is complex, i.e., polygenic. That mitted as autosomal dominant traits with incomplete penetrance or a genetic factor is operative in primary generalized tonic-clonic perhaps in a more complicated manner. In the partial, or focal, seizures is suggested by the finding of a familial incidence in 5 to epilepsies (which is the form that seizures take in two-thirds of 10 percent of such patients and, in particular families, the inheri- adults and almost half of the children with epilepsy), the role of tance of a generalized seizure disorder through specific chromo- heredity is not nearly so clear. Yet in numerous studies there has somal regions (Berkovic). The importance of genetic factors in the been a greater-than-expected incidence of seizures, EEG abnor- primary (idiopathic) epilepsies is also underscored by evidence malities, or both among first-degree relatives. Among the familial from twin studies; in six major series, the overall concordance rate cortical epilepsies, both a temporal and frontal lobe type are in- was 60 percent for monozygotic twins and 13 percent for dizygotic herited in a polygenic fashion or in an autosomal dominant pattern. pairs. Undoubtedly also inherited is the tendency to develop simple fe- In only a few of the idiopathic seizure disorders is a simple brile convulsions, though the mode of inheritance is uncertain. (mendelian) pattern of inheritance recognized. These include a sub- The genetics of the epileptic disorders has been reviewed in group of benign neonatal familial convulsions inherited as an au- detail by Steinlein, Delgado-Escueta and colleagues, Hirose and tosomal dominant trait (Leppert) and a similar disorder of infantile associates, Malafosse and Moulard, and Anderson and Hauser, onset and a benign myoclonic epilepsy of childhood (autosomal whose articles are recommended. recessive). Particularly informative are a special group of epileptic dis- CLINICAL APPROACH TO THE orders in which monogenic genetic defects have been found to be EPILEPSIES related to ion channels or neurotransmitter receptors (Table 16-3). These were mentioned earlier in the discussion of the physiology The physician faced with a patient who seeks advice about an ep- of seizures and, despite their rarity, they suggest that idiopathic isodic disorder of nervous function must determine, first, whether epilepsy may be due to a disruption in the function of these chan- the episode in question is indeed a seizure; if so, she must determine nels. Functional studies suggest that the consequences of almost all its pattern and other characteristics; and, finally, she must undertake of these mutations are to enhance overall neuronal excitability. Ex- a search for its cause. In the diagnosis of epilepsy, history is the amples include nocturnal frontal lobe epilepsy, which may present key; in most adult cases the physical examination is relatively un- short as a partial seizure (in which the offending mutations are in sub- revealing. The examination in infants and children is of greater stand
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cap height Table 16-3 base of text Monogenic epileptic disorders
GENE PROTEIN INVOLVED Channelopathies Sodium channels
Familial generalized seizures with febrile SCN1A,B, (GABAA) Sodium channel subunits, less often, GABA seizures “plus”; see text receptor Benign familial neonatal convulsions SCN2A Sodium channel subunits Potassium channels Benign infantile epilepsy KCNQ2,3 Potassium channel subunits Episodic ataxia type 1 with partial epilepsy KCNA1 Ligand-gated channels Autosomal dominant nocturnal frontal seizures CHRNA 2,4 Nicotinic acetylcholine receptor subunits
Familial generalized and febrile seizures GABRG2 GABAA receptor subunit
Juvenile myoclonic epilepsy GABRA1 (CACNB4) GABAA receptor subunit, less often, calcium Calcium channels channel subunit Episodic ataxia type 2 with spike-wave CACNA1A Calcium channel subunit seizures Malformations of cortical development Holoprosencephaly, generalized epilepsy SHH, PTCH, ZIC2, SIX3, TGIF Sonic hedgehog, SHH receptor, transcription factors Schizencephaly, generalized epilepsy EMX2 Homeodomain protein Tuberous sclerosis, generalized epilepsy TSC1, 2 Hamartin, tuberin Lissencephaly, generalized epilepsy LIS1 Platelet-activating factor acid hydrolase Double cortex syndrome, generalized epilepsy DCX Doublecortin Heterotopia, generalized epilepsy FLN1 Filamin1 Fukuyama muscular dystrophy, lissencephaly, FCMD Fukutin generalized epilepsy Walker-Warburg syndrome, generalized POMT1 O-mannosyl transferase epilepsy Muscle-eye-brain disease, generalized epilepsy MEB Lycosyltransferase, PMGnT1 Angelman syndrome: myoclonic, tonic-clonic, UBE3A Ubiquitin-protein ligase atonic seizures Progressive myoclonic epilepsies (PME) Unverricht-Lundborg disease with PME EPM1 Cystatin B Lafora body disease with PME EPM2A Laforin, protein tyrosine phosphatase Myoclonic epilepsy with ragged red fibers tRNAlys Mitochondrial lysine tRNA Dentatorubro-pallidoluysian atrophy with PME DRPLA Atrophin-1 Gaucher disease PSAP -glucocerebrosidase Sialidosis type I NEU1 Sialidase Ceroid lipofuscinosis (CLN) and PME CLN CLN2, CLN3, CLN5, CLN6 also cause generalized, atonic and atypical absence seizures Mixed seizure types Lipoid proteinosis and temporal lobe epilepsy ECM1 Extracellular matrix protein 1 Temporal lobe epilepsy LGI1 Leucine-rich glioma inactivated protein CLN8; progressive non-myoclonic epilepsy CLN8 Membrane protein in endoplasmic reticulum with retardation value, since the finding of dysmorphic and cutaneous abnormalities EEG monitoring, either in the hospital or with portable equipment allow the diagnosis of a large number of cerebral diseases that give at home. Other forms of testing—e.g., cardiac stress tests, Holter rise to epilepsy. monitors, tilt-table testing, long-term patient-activated cardiac Several laboratory studies should routinely be included in the monitors, and sleep studies—are sometimes indicated in order to initial diagnostic workup—complete blood count (CBC), blood exclude some of the nonepileptic disorders listed below. chemistries, liver and thyroid function tests, EEG, and, most im- The conditions most likely to simulate a seizure are syncope portantly, an imaging study of the brain, preferably MRI. CT scan- and transient ischemic attacks, but also to be considered are mi- ning may be the only feasible study in an emergency or for very graine, unexplained falls (drop attacks), sleepwalking and rapid- short young children. Some patients may later need protracted video/ eye-movement (REM) sleep behavior disorder, panic attacks, hy- stand
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cap height poglycemia, cataplexy, paroxysmal ataxia and choreoathetosis, slowly than those of a seizure, and by their nature TIAs tend to base of text recurrent transient global amnesia, and hysterical pseudoseizures. produce a focal loss of function without convulsions. However, a Often, in emergency departments, it is difficult to differentiate the “limb-shaking” TIA and convulsive phenomena at the outset of postictal effects of an unwitnessed seizure from mild confusion basilar artery occlusion may be nearly impossible to distinguish following cerebral concussion or from a brief loss of consciousness from epilepsy. produced by a subarachnoid hemorrhage. Drop attacks (falling to the ground without loss of conscious- The clinical differences between a seizure and a syncopal at- ness) remain an enigma (page 329). In most cases, we have failed tack are considered in Chap. 18. Here it is emphasized that no to substantiate their association with circulatory disturbances of the single criterion stands inviolate. The authors have erred in mistak- vertebrobasilar system and seldom have we observed them to be ing akinetic seizures for simple faints and vasovagal and cardiac an expression of atonic or myoclonic epilepsy, but such an occur- faints for seizures. If blood is tested after the episode in question, rence has been reported with the Lennox-Gastaut syndrome. In elevation in creatine kinase (persistent for hours) and prolactin (for some instances they represent simple unexpected falls, especially up to 10 min) may be helpful in the diagnosis of a convulsive in stout older women who are sedentary. The degenerative disease seizure. Postictal confusion, incontinence, and a bitten tongue progressive supranuclear palsy may also present itself in this way clearly bespeak seizure rather than syncope. Absence attacks may (Chap. 39). be difficult to identify because of their brevity. Helpful maneuvers Regarding the distinction of narcolepsy, paroxysmal ataxia or are to have the patient hyperventilate in order to evoke an attack choreoathetosis, transient global amnesia, hysterical fugues, panic or to observe the patient counting aloud for 5 min. Those with attacks, and REM sleep behavior disorder from seizures, it is suf- frequent absence attacks will pause or skip one or two numbers. ficient to be aware of the diagnostic criteria for each of these con- The diagnosis of complex partial seizures is the most difficult. ditions. These attacks are so variable and so often induce disturbances of behavior and psychic function—rather than obvious interruptions The Probable Causes of Seizure(s) at of consciousness—that they may be mistaken for temper tantrums, Different Age Periods hysteria, sociopathic behavior, or acute psychosis. The careful (Table 16-4 and Fig. 16-3) questioning of witnesses of an attack is essential. Verbalizations that cannot be remembered, walking aimlessly, or inappropriate Having concluded that the neurologic disturbance under consider- actions and social behavior are characteristic. As stated above, we ation is one of seizure, the next issue is to identify the type of have placed emphasis on amnesia for the events of at least part of seizure; indeed, this determines in most cases the nature of treat- the seizure as a crucial criterion for the diagnosis of temporal lobe ment. Since there are so many seizure types, especially in childhood epilepsy. In all obscure forms of epilepsy, prolonged EEG and and adolescence, each one tending to predominate in a certain age video monitoring may prove diagnostic. A mild complex partial period, a clinical advantage accrues to considering seizure prob- seizure, consisting of a brief loss of consciousness and lip-smack- lems from just this point of view, i.e., the problem of epilepsy as ing, may be mistaken for an absence unless it is kept in mind that it presents in each period of life, along with the neurologic and the former (but not the latter) is commonly followed by a period EEG findings, as well as the response to drugs, etiology, and prog- of confusion and dysphasia when the language areas are involved. nosis. Epilepsy complicated by states of constitutional mental dull- Figure 16-3 displays the frequency of each seizure type and ness and confusion poses special problems in diagnosis. Most ep- the main causes of seizures in each age group. These data are as- ileptic patients seen in a general hospital or in office practice show sembled from various sources and are approximate, but they high- no evidence of mental retardation, regardless of the type of seizure. light several points of clinical importance. First, implicit is the fact Undoubtedly, seizures are more common in the mentally retarded, that the age of the patient greatly affects the incidence of certain but recurrent seizures in themselves seldom cause intellectual de- seizure types; e.g., absence and myoclonic seizures are relatively terioration (Ellenberg et al); when this does happen, one should more common in children and adolescents. Furthermore, the un- suspect an underlying degenerative or hereditary metabolic disease. derlying causation varies greatly by age as discussed further on. An exception to this statement is the patient with frequent and uncontrolled subclinical seizures (nonconvulsive status) who is Neonatal Seizures The neonatologist is often confronted by an drugged or in a postseizure psychotic state. Hospital admission and infant that begins to convulse in the first days of postnatal life. a systematic study of the seizure state and drug levels are necessary In most instances, the seizures are fragmentary—an abrupt move- in the analysis of this problem. ment or posturing of a limb, stiffening of the body, rolling up of Migraine should not be mistaken for a seizure, for reasons the eyes, a pause in respirations, lip-smacking, chewing, or bi- discussed on page 153. One feature of the focal neurologic dis- cycling movements of the legs. Even the experienced observer order of classic migraine is particularly helpful—namely, the pace may have difficulty at times in distinguishing seizure activity of the sequence of cerebral malfunction over a period of minutes from the normal movements of the neonate. If manifest seizures rather than seconds, as in partial epilepsy. Even this criterion may are frequent, the diagnosis is less difficult. The seizures correlate fail occasionally, especially if both migraine and partial seizures with focal or multifocal cortical discharges; however, as is the are joined, e.g., as expressions of a vascular malformation of the case with most EEG changes in neonates, these are poorly formed brain. and less distinct than seizure discharges in later life. Presumably Useful in the identification of a transient ischemic attack the immaturity of the cerebrum prevents the development of a (TIA) and its separation from partial epilepsy are the patient’s age, fully organized seizure pattern. The EEG is nonetheless helpful evidence of disease of the heart or carotid arteries, and the lack of in diagnosis. Periods of EEG suppression may alternate with disorder of consciousness or amnesia. Again, if the ischemic attack sharp or slow waves, or there may be discontinuous theta activity. short is marked by an evolution of symptoms, they tend to develop more Unfortunately, electrical seizure activity may be unattended by stand
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cap height Table 16-4 bolic disorders may lead to seizures in the first week or two of life base of text Causes of recurrent seizures in different age groups (see also and are expressive of a more diffuse encephalopathy. Fig. 16-3) Benign forms of neonatal seizures have also been identified. Plouin has described a form of benign neonatal clonic convulsions a AGE OF ONSET PROBABLE CAUSE beginning on days 2 and 3, up to day 7, in which there were no Neonatal Congenital maldevelopment, birth specific EEG changes. The seizures then remit. The inheritance is injury, anoxia, metabolic disorders autosomal dominant. There are other nonfamilial cases with onset (hypocalcemia, hypoglycemia, on days 4 to 6, wherein the partial seizures may even increase to
vitamin B6 deficiency, biotinidase status epilepticus; the EEG consists of discontinuous theta activity. deficiency, phenylketonuria, and In both these groups, the outlook for normal development is good others) and seizures seldom recur later in life. There are also benign forms Infancy (1–6 months) As above; infantile spasms; West of polymyoclonus without seizures or EEG abnormality in this age syndrome period. Some occur only with slow-wave sleep or feeding. They Early childhood (6 Infantile spasms, febrile convulsions, disappear after a few months and require no treatment. A form of months–3 years) birth injury and anoxia, infections, benign nocturnal myoclonus in the neonate has also been docu- trauma, metabolic disorders, cortical mented. When therapy is necessary, phenobarbital has been pre- dysgenesis, accidental drug poisoning ferred. Childhood (3–10 Perinatal anoxia, injury at birth or later, years) infections, thrombosis of cerebral Infantile Seizures (Occurring in the First Months, Up to 2 arteries or veins, metabolic disorders, Years) Neonatal seizures may continue into the infantile period, cortical malformations, Lennox- or seizures may begin in an infant who seemed to be normal up to Gastaut syndrome, “idiopathic,” the time of the first convulsive attack. The most characteristic pat- probably inherited, epilepsy tern at this age is the massive sudden myoclonic jerk of head and (Rolandic epilepsy) arms leading to flexion or, less often, to extension of the body Adolescence (10–18 Idiopathic epilepsy, including (infantile spasms, salaam spasms). This form, known as the West years) genetically transmitted types, juvenile syndrome as described earlier, is the most threatening of all infan- myoclonic epilepsy, trauma, drugs tile seizures. We have observed the same seizure type in infants Early adulthood Idiopathic epilepsy, trauma, neoplasm, with tuberous sclerosis (diagnosed in infancy by dermal white (18–25 years) withdrawal from alcohol or other spots), phenylketonuria, or Sturge-Weber angiomatosis, but most sedative drugs often it is associated with other diseases beginning in this age pe- Middle age (35–60 Trauma, neoplasm, vascular disease, riod. West syndrome is probably a metabolic encephalopathy of years) alcohol or other drug withdrawal unknown type or, in some cases, a cortical dysgenesis (Jellinger) Late life (over 60 Vascular disease (usually and is identified by an EEG picture of large bilateral slow waves years) postinfarction), tumor, abscess, and multifocal spikes (hypsarrhythmia). Again, there is a benign degenerative disease, trauma form of infantile myoclonic epilepsy in which repetitive myoclonic jerking occurs in otherwise normal infants whose EEGs show only a Meningitis or encephalitis and their complications may be a cause of seizures at any spike waves in early sleep. age. This is true also of severe metabolic disturbances. In tropical and subtropical However, when the myoclonus begins in infancy with fever countries, parasitic infection of the CNS is a common cause. and unilateral or bilateral clonic seizures or with partial seizures followed by focal neurologic abnormalities, there is a likelihood of clinical manifestations. An early onset of myoclonic jerks, either developmental delay. The latter types are sometimes referred to as fragmentary or massive, with an EEG pattern of alternating sup- complicated febrile seizures, but, as indicated above, they must be pression and complex bursts of activity is particularly ominous distinguished from the benign familial febrile seizure syndrome. according to Aicardi. Another extremely malignant form of neo- Infantile spasms cease by the fifth year and are replaced by partial natal seizure evolving later into infantile spasms and Lennox- and generalized grand mal seizures. They do not respond well to Gastaut syndrome and leaving in its wake severe brain damage the usual anticonvulsant medications. was described by Ohtahara. Most of the reported patients were left mentally retarded (Brett). Seizures Presenting in Early Childhood (Onset during the First Neonatal seizures occurring within 24 to 48 h of a difficult 5 to 6 Years) At this age, the first burst of seizures may take the birth are usually indicative of severe cerebral damage, usually an- form of status epilepticus and, if not successfully controlled, may oxic, either antenatal or parturitional. Such infants often succumb, end fatally. Or the convulsive state may present around the age of and about half of the survivors are seriously handicapped. Seizures 4 years as a focal myoclonus with or without astatic seizures, atyp- having their onset several days or weeks after birth are more often ical absence, or generalized tonic-clonic seizures. The EEG, re- an expression of acquired or hereditary metabolic disease. In this peated if initially normal, is most helpful in diagnosis; it reveals a latter group, hypoglycemia is the most frequent cause; another, paroxysmal 2- to 2.5-per-second spike-and-wave pattern on a back- hypocalcemia with tetany, has become infrequent. A hereditary ground of predominant 4- to 7-Hz slow waves. Many of these cases form of pyridoxine deficiency is a rare cause, sometimes also in- qualify as the Lennox-Gastaut syndrome, are difficult to treat, and ducing seizures in utero and characteristically responding promptly are likely to be associated with developmental retardation (see page to massive doses (100 mg) of vitamin B6 given intravenously. Bio- 274). The MRI may be helpful in identifying a birth injury or cor- tinidase deficiency is another rare but correctable cause. Nonketotic tical dysgenesis. short hyperglycemia, maple syrup urine disease, as well as other meta- In contrast, the more typical absence, with its regularly recur stand
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cap height ring three-per-second spike-and-wave Cause of seizure base of text EEG abnormality, also begins in this 70 age period (rarely before 4 years) and 60 Cogenital carries a good prognosis. This seizure 50 Trauma disorder responds well to medications, 40 as indicated further on. Its features are Infection 30 Cerebrovascular fully described on page 274. 20 Tumor A number of partial epilepsies 10 Degenerative may appear for the first time during this 0 age period and carry a good prognosis, Percent of incident cases 0–14 15–34 36–64 >65 i.e., the neurologic and intellectual ca- Years pacities remain relatively unimpaired Figure 16-3. Distribution of the main causes of seizures at different ages. Evident is the prevalence of and seizures may cease in adolescence. congenital causes in childhood and the emergence of cerebrovascular disease in older patients. (Adapted These disorders begin between 3 and from several sources including Hauser and Annegers and the texts of Engel and of Pedley.) 13 years of age, and there is often a familial predisposition. Most are marked by distinctive focal spike activity that is greatly accentuated all antiepileptic drugs. The use of full doses of corticosteroids, if by sleep (see above, in reference to benign childhood epilepsy with started within the first year of the disease, proved beneficial in 5 centrotemporal or occipital spikes). In one form, unilateral tonic or of the 8 patients treated by Chinchilla and colleagues. Repeated clonic contractions of the face and limbs recur repeatedly with or plasma exchanges and immune globulin have been tried, but the without paresthesias; anarthria follows the seizure. There are cen- results are difficult to interpret. When the disease is extensive and tral and temporal spikes in the EEG interictally. According to Gas- unilateral, neurosurgeons have in the past resorted to partial hemi- taut, the focus may involve an occipital lobe with EEG spiking on spherectomy. The authors have cared for a number of such patients eye closure. An acquired aphasia was noted by Landau and Kleffner with the same discouraging results. to mark the beginning of an illness in which there are partial or generalized motor seizures and multifocal spike or spike-and-wave Seizures in Later Childhood and Adolescence These represent discharges in the EEG. Tumor and arteriovenous malformation are the most common epileptic problem in general practice. Here, we rare causes in this age group. face two different issues: one relates to the nature and management Rasmussen Encephalitis In other rare cases, a lesion, usually of the first seizure in an otherwise normal young person and the identified by biopsy, takes the form of a chronic focal encephalitis. other to the management of a patient who has had one or more In 1958, Rasmussen described three children in each of whom the seizures at some time in the past. With respect to the first, a search clinical problem consisted of intractable focal epilepsy in associ- for a cause by CT, MRI, CSF examination, and EEG rarely dis- ation with a progressive hemiparesis. The cerebral cortex disclosed closes a tumor or a vascular malformation and the epilepsy is then a mild meningeal infiltration of inflammatory cells and an enceph- classed as idiopathic. The type of seizure that first brings the child alitic process marked by neuronal destruction, gliosis, neurono- or adolescent to medical attention is most likely to be a generalized phagia, some degree of tissue necrosis, and perivascular cuffing. tonic-clonic convulsion and often marks the beginning of a juvenile Many additional cases were soon uncovered, and by 1991, in a myoclonic epilepsy, as described on page 275. In the second type publication devoted to this subject (edited by Andermann), Ras- of case, in which there had been some type of seizure at an earlier mussen was able to summarize the natural history of 48 personally period, one should suspect a developmental disorder, parturitional observed patients. hypoxic-ischemic encephalopathy (birth injury), or one of the he- The expanded view of the syndrome has added several inter- reditary metabolic diseases. esting features. All the patients were children aged 3 to 15 years, Several groups of patients fall between these two distinct more girls than boys. Half of them had epilepsia partialis continua. types. Development may have been slightly delayed, but reportedly The progression of the disease led to hemiplegia or other deficits no seizures had occurred earlier in life. Closer investigation may and brain atrophy in most cases. The CSF has shown pleocytosis disclose absence seizures, not always recognized as such by parents and sometimes oligoclonal bands. Focal cortical and subcortical or teachers, and a typical absence EEG, which points more directly lesions have been well visualized by MRI and are bilateral in some to a genetic factor and to a more favorable prognosis. cases. The neuropathology of five fully autopsied cases revealed When the seizures are an expression of a long-standing epi- extensive destruction of the cortex and white matter with intense leptic focus or foci that had been associated with mental back- gliosis but with lingering inflammatory reactions. The finding of wardness, scholastic failure, and inadequacy of social adjustment, antibodies to glutamate receptors in a proportion of patients has the diagnostic and therapeutic problem becomes much more diffi- raised interest in an immune causation (see review by Antel and cult and demanding. Poor observations by the family, muddled Rasmussen). An autoimmune hypothesis has been supported by the thinking, and bizarre ideation on the part of the patient as well as findings of Twyman and colleagues that these antibodies cause poor compliance with therapy may pose problems as difficult as seizures in rabbits and lead to the release of the neurotoxin kainate the seizures themselves. Some patients of this latter group will in cell cultures. However, Wiendl’s group and others have found eventually fall into the category of epilepsy with complex partial these antibodies in many types of focal epilepsy and question their seizures. In adulthood, the seizures may continue to interfere with specificity for the Rasmussen type of encephalitis. work, marriage, and family relationships. In the interictal periods, The unrelenting course of the disease has defied medical ther- the patients may exhibit bursts of bad temper, and they commonly apy. In some patients the process has eventually burned out, but in have wide mood swings of sadness and anger or elation. As indi- short those with continuous focal epilepsy the seizures continued despite cated earlier, paranoid ideation or a frank hallucinatory-delusional stand
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cap height psychosis sometimes appears and lasts for weeks after a single encephalitis, including those derived from HIV infection, both di- base of text seizure, without any specific EEG changes. rectly and indirectly; with toxoplasmosis and brain lymphoma; and In the large group with intractable seizures in early life, many in subacute sclerosing panencephalitis. In tropical countries, cysti- of which are indiscriminately called febrile seizures, nearly half cercosis and tuberculous granulomas of the brain are very common end up in the group identified as temporal lobe epilepsies. Hutten- causes of epilepsy. Seizure(s) without fever or stiff neck may be the locher and Hapke, in a follow-up study of 145 infants and children initial manifestation of syphilitic meningitis, a fact worth noting with with intractable epilepsy, found that the majority had borderline or the increasing incidence of this process in AIDS patients. subnormal intelligence. This group stands in contrast to the group Endogenous Metabolic Encephalopathies Uremia is a condition of otherwise normal adolescents with a first seizure whose scho- with a strong convulsive tendency. Of interest is the relation of lastic progress and social and emotional adjustment are little if at seizures to the development of anuric renal failure, generally from all affected. acute tubular necrosis but occasionally due to glomerular disease. Juvenile myoclonic epilepsy also has its onset during this age Total anuria may be tolerated for several days without the appear- period. As described earlier, it is identified by intermittent my- ance of neurologic signs, and then there is an abrupt onset of twitch- oclonic jerks when the patient is tired or after the ingestion of ing, trembling, myoclonic jerks, and generalized motor seizures. alcohol. Seizures are usually grand mal but are infrequent. The Tetany may be added. The motor display, one of the most dramatic EEG shows a characteristic polyspike pattern, and treatment with in medicine, lasts several days until the patient sinks into terminal certain anticonvulsants is very successful at suppressing the sei- coma or recovers, depending on the outcome of the renal disease zures and myoclonus (see page 295). and its treatment by dialysis. When this twitch-convulsive syn- Finally, a first generalized seizure may bring to attention an drome accompanies lupus erythematosus, seizures of undetermined adolescent who is abusing alcohol or another drug. Usually it is cause, or generalized neoplasia, one should suspect it has its basis difficult from the clinical information alone to determine the type in renal failure. and quantity of the drug(s) and the setting in which the seizure Other acute metabolic illnesses and electrolytic disorders occurred—whether in relation to overdose or withdrawal. While complicated by generalized and multifocal motor seizures are hy- steps must be taken to exclude an infection of the nervous system, ponatremia and its opposite, a hypernatremic hyperosmolar state, vascular occlusion, or trauma, the more important issue is generally thyrotoxic storm, porphyria, hypoglycemia, hyperglycemia, hypo- not the seizure but the addiction and its control. magnesemia, and hypocalcemia. In all these cases rapidly evolving Regarding treatment, opinion is divided on whether treatment electrolyte abnormalities are more likely to cause seizures than is required for the older child or adolescent who comes to medical those occurring gradually. For this reason it is not possible to as- attention because of a first seizure. When a large number of such sign absolute levels of electrolyte, BUN, or glucose concentrations cases have been left untreated, such as in the series reported by above or below which seizures are likely to occur. Lead (in chil- Hesdorfer and colleagues, the risk of another seizure over 10 years dren) and mercury (in children and adults) are the most frequent was 13 percent unless the first episode was status epilepticus, in of the metallic poisons that cause convulsions. which case the risk was 41 percent. Age, sex, and the circumstances In most cases of seizures due to metabolic and withdrawal of the seizure (withdrawal from drugs or alcohol, myoclonic epi- states, treatment with anticonvulsants is usually not necessary as sodes, family history, etc.) all figured into the risk. long as the underlying disturbance is rectified. Indeed, anticon- vulsants are often ineffective if the metabolic disorder persists. Seizures with Onset in Adult Life and Secondary to Medical Generalized seizures, with or without twitching, may occur in Disease Several primary diseases of the brain often announce the advanced stages of many other illnesses, such as hypertensive themselves by an acute convulsive state, particularly primary and encephalopathy, sepsis—especially gram-negative septicemia with metastatic brain tumors; these are discussed further on in the sec- shock—hepatic stupor, and intractable congestive heart failure. tion on seizures of late adult life. Here we focus on generalized Usually, seizures in these circumstances can be traced to an asso- medical disorders as causes of single and repeated seizures. ciated metabolic abnormality and are revealed by appropriate stud- Withdrawal Seizures The possibility of abstinence seizures in ies of the blood. patients who had chronically abused alcohol, barbiturates, or ben- Medications as a Cause of Seizures A large number of medi- zodiazepine sedative drugs must always be considered when sei- cations can cause seizures, usually when toxic blood levels are zures occur for the first time in adult life (or even in adolescence). attained. The antibiotic imipenem and excessive doses of other pen- Suspicion of this mechanism is raised by the stigmata of alcohol icillin congeners will on occasion cause seizures, particularly if abuse or a history of prolonged nervousness and depression re- renal failure leads to drug accumulation. Cefapime, a fourth- quiring sedation. Also, sleep disturbance, tremulousness, disori- generation cephalosporin, widely used for the treatment of gram- entation, illusions, and hallucinations are often associated with the negative sepsis, can result in status epilepticus, especially if given convulsive phase of the illness. Seizures in this setting may occur in excessive dosage (Dixit et al). The tricyclic antidepressants, bu- singly, but more often in a brief flurry, the entire convulsive period propion (Wellbutrin), and lithium may cause seizures, particularly lasting for several hours and rarely for a day or longer, during in the presence of a structural brain lesion. Lidocaine and aminoph- which time the patient may be unduly sensitive to photic stimula- ylline are known to induce a single convulsion if administered too tion. Alcohol and other drug-related seizures are discussed in more quickly or in excessive doses. The use of the analgesic tramadol detail on pages 1008 and 1022. has also been associated with seizures. Curiously, the anesthetic Infections An outburst of seizures is also a prominent feature propofol, which is discussed further on as a potent anticonvulsant of all varieties of bacterial meningitis, more so in children than in the treatment of status epilepticus, has caused seizure and in adults. Fever, headache, and stiff neck usually provide the clues marked myoclonic phenomena in some patients. These may occur to diagnosis, and lumbar puncture yields the salient data. Myo- during induction or emergence from anesthesia or as a delayed short clonic jerking and seizures appear early in acute herpes sim- problem (Walder et al). stand plex encephalitis and other forms of viral, treponemal, and parasitic The list of medications that at one time or another have been long
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cap height associated with a convulsion is long, and if no other explanation ministration of vitamin K 20 mg/day during the eighth month or base of text for a single seizure is evident, the physician is advised to look up 10 mg IV 4 h before birth and 1 mg IM to the neonate. The con- in standard references the side effects of the drugs being given to ventional anticonvulsants also seem to be safe for the baby during the patient. In a few of our otherwise healthy adult patients, extreme breast-feeding in that only small amounts are excreted in lactated sleep deprivation coupled with ingestion of large doses of antibi- milk. For example, carbamazepine in human milk is found to be otics or adrenergic medications or other remedies that are used 40 percent of the mother’s serum concentration, and this results in indiscriminately for the symptomatic relief of colds has been the a neonatal blood level that is below the conventionally detectable only plausible explanation after extensive search for the cause of a amount. Phenytoin is excreted at 15 percent of maternal serum single or doublet seizure. concentration, and valproate, being highly protein-bound, is vir- Global Arrest of Circulation and Cerebrovascular Diseases tually absent in breast milk. No adverse effects have been attributed Cardiac arrest, suffocation or respiratory failure, carbon monoxide to these small amounts of drug. poisoning, or other causes of hypoxic encephalopathy tend to in- The special issue of the teratogenicity of antiepileptic drugs duce diffuse myoclonic jerking and generalized seizures as cardiac is addressed further on. function is resumed. The myoclonic-convulsive phase of this con- Eclampsia (See also Chap. 34.) This syndrome appears during dition may last only a few hours or days, in association with coma, the last trimester of pregnancy and may announce itself by hyper- stupor, and confusion; or it may persist indefinitely as an intention tension and convulsions; the latter are generalized and tend to occur myoclonus-convulsive state (Lance-Adams syndrome). in clusters. The standard practice is to induce labor or perform Convulsive seizures are uncommon in the acute or evolving cesarean section and manage the seizures as one would manage phases of an arterial stroke. The ischemic convulsive phenomena those of hypertensive encephalopathy (of which this is one type). of a “limb-shaking TIA” and a burst of generalized clonic motor The administration of magnesium sulfate continues to be the fa- activity during basilar artery occlusion have been mentioned earlier vored treatment by obstetricians for the prevention of eclamptic but are uncommon. Only exceptionally will acute embolic infarc- seizures; two randomized trials have re-established its value in pre- tion of the brain cause a focal fit at its onset. With these infrequent venting seizures in pre-eclamptic women (Lucas et al) and in avoid- exceptions, a new seizure should not be attributed to an acute ar- ing a second convulsion once one had occurred (Eclampsia Trial terial occlusion in the cerebrum. More relevant is the fact that em- Collaborative Group). Magnesium sulfate, 10 g IM, followed by bolic infarcts involving the cortex later, after an interval of months 5 g every 4 h, proved comparable to standard doses of phenytoin or longer, become epileptogenic in almost 10 percent of cases. as prophylaxis for seizures. Our colleagues use a regimen of 4 g Thrombotic infarcts are almost never convulsive at their onset. IV over 5 to 10 min followed by a maintenance dose of 5 g every In contrast, cortical venous thrombosis with underlying ische- 4 h IM or 1 to 2 g/h IV. Whether magnesium is as effective in the mia and infarction is highly epileptogenic. The same is true for management of active convulsions of toxemia remains uncertain. hypertensive encephalopathy and thrombotic thrombocytopenic In nontoxic gestational epilepsy, about 25 percent of patients are purpura (TTP), which has a strong tendency to cause nonconvulsive found to have some disease (neoplastic, vascular, or traumatic) that status epilepticus. The rupture of a saccular aneurysm is sometimes will persist. marked by one or two generalized convulsions. Subcortical cerebral hemorrhages, spontaneous or traumatic, occasionally become Focal or Generalized Seizures in Late sources of recurrent focal seizures. Adult Life Seizures with Acute Head Injury It is not uncommon for severe concussion to be followed by one or more brief convulsions (see Hauser and Kurland have reported a marked increase in the inci- Chap. 35). The appearance is similar in most cases to the clonic dence of seizures as the population ages—from 11.9 per 100,000 twitching and brief tonic phase that accompanies a faint. From time in the 40- to 60-year age group to 82 per 100,000 in those 60 years to time, a prolonged clonic convulsion occurs. The nature of this of age or older. A person in the latter age group who begins to event, whether originating in the reticular formation as a compo- have seizures of either partial or generalized type is always to be nent of concussion or from some disruption of cortical activity, is suspected of harboring a primary or secondary tumor or an infarct not clear. Almost invariably in our experience, the EEG recorded that had not declared itself clinically. This is a matter usually settled hours or a day later is normal, and imaging procedures are likewise by the neurologic examination and by CT or MRI. Tumor, either normal or show a small contusion. There is little to guide one in primary or secondary, will be found to account for about half the treatment of these patients; we tend to give a course of anticon- cases of seizures occurring for the first time in late adult life. In vulsant medications lasting several months. Another EEG is taken our clinical material, almost 10 percent of patients with infarction before discontinuing the medications. involving the cerebral cortex later developed recurrent partial or generalized seizures, but most published series cite a lower pro- Seizures during Pregnancy Here one contends with two types of portion. According to Sung and Chu, previous infarcts are by far problem: one, the woman with epilepsy who becomes pregnant; the the most common lesions underlying status epilepticus in late adult other, the woman who has her first seizure during pregnancy. In respect life, but our experience has been that old trauma is as common. to the first group, about half of the epileptic women who become Cortical and subcortical encephalomalacia, the result of previous pregnant have no change in seizure frequency or severity; in about 25 traumatic contusions, is a particularly important cause of seizures percent, the frequency increases; and in an equal number, it lessens. among alcoholics; the lesions are revealed by brain imaging and In a large cohort of such women, there was a slight increase in the are typically located in the anterior frontal and temporal lobes. number of stillbirths and a doubling in the expected incidence of men- Brain abscess and other inflammatory and infectious illnesses are tal retardation and nonfebrile seizures in their offspring. less common except in tropical regions. Seizures as a result of
Issues regarding a coagulopathy in the fetus exposed to phe- Alzheimer and other degenerative diseases do occur but are un- short nobarbital and certain of the other drugs are well known to obste- common. stand tricians and pediatric specialists and are treated with the oral ad- In the not infrequent cases of an adult with a first seizure that long
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EFFECTIVE SERUM BLOOD USUAL DOSAGE GENERIC TRADE PRINCIPAL THERAPEUTIC HALF-LIFE, LEVEL,a NAME NAME CHILDREN, MG/KG ADULTS, MG/DAY INDICATIONS HOURS G/ML Major anticonvulsants used as monotherapy Valproic acid Depakote 30–60 1000–3000 Generalized tonic-clonic, partial, 6–15 50–100 absence, myoclonic Phenytoin Dilantin 4–7 300–400 Generalized tonic-clonic, partial, 12–36 10–20 absence, myoclonic Carbamazepine Tegretol 20–30 600–1200b Generalized tonic-clonic, partial 14–25 4–12 Phenobarbital Luminal 3–5 (8 for infants) 90–200 Generalized tonic-clonic, partial 40–120 15–40 Lamotrigine Lamictal 0.5 3–500 Generalized 15–60 Adjuvant and special use anticonvulsants Topiramate Topamax 400 Generalized tonic-clonic, atypical 20–30 absence, myoclonic, partial Vigabatrin 4000 Partial and secondary generalized, 20–40 Lennox-Gastaut Tiagabine Gabitril 30–60 Partial and secondary generalized, 7–9 Gabapentin Neurontin 30–60 900–1800b Partial and secondary generalized, 5–7 Primidone Mysoline 10–25 750–1500b Generalized tonic-clonic, partial 6–18 5–12 Ethosuximide Zarontin 20–40 750–1500 Absence 20–60 50–100 Methsuximide Celontin 10–20 500–1000 Absence 28–50 40–100 ACTH 40–60 Units daily Infantile spasms Clonazepam Klonopin 0.01–0.2 2–10 Absence, myoclonus 18–50 0.01–0.07 Anticonvulsants for status epilepticus (initial loading or continuous infusion doses shown)c—phenytoin and phenobarbital used in doses higher than shown above Diazepam Valium 0.15–2 2–20 Status epilepticus Lorazepam Ativan 0.03–0.22 2–20 Status epilepticus Midazolam Versed 0.1–0.4 mg/kg/h Status epilepticus Propofol Diprivan 2.5–3.5 2–8 mg/kg/h Status epilepticus Fosphenytoin Cerebyx 30–50 mg 1000–1500 Status epilepticus 10–20 a Average trough values. b May require slow dose escalation. c Administered intravenously. remains unexplained after thorough evaluation, it has been our The Use of Antiepileptic Drugs— practice to administer an anticonvulsant and to re-evaluate the sit- General Principles uation in a matter of 6 to 12 months, with the goal of eventually discontinuing medication. Usually, a second MRI and EEG are The use of antiepileptic drugs is the most important facet of treat- performed to exclude focal abnormalities that were not appreciated ment. In approximately 70 percent of all patients with epilepsy, the during the initial evaluation, but often these studies are again un- seizures are controlled completely or almost completely by the use revealing. This approach has been prompted by data such as those of antiepileptic drugs; in an additional 20 to 25 percent, the attacks of Hauser and colleagues, who found that about one-third of pa- are significantly reduced in number and severity. The most com- tients with a single unprovoked seizure will have another seizure monly used drugs are listed in Table 16-5, along with their dosages, within 5 years; the risk is even greater if there is a history of sei- effective blood levels, and serum half-lives. Because of the long zures in a sibling, a complex febrile convulsion in childhood, or a half-lives of phenytoin, phenobarbital, and ethosuximide, these spike-and-wave abnormality in the EEG. Moreover, the risk of re- drugs need be taken only once daily, preferably at bedtime. Val- currence is greatest in the first 24 months. In patients with two or proate and carbamazepine have shorter half-lives, and their admin- three unexplained seizures, three-quarters have further seizures in istration should be spaced during the day. It is also useful to be the subsequent 4 years. familiar with the serum protein-binding characteristics of antiepi- leptic drugs and the interactions among these drugs, and between TREATMENT OF EPILEPSY antiepileptic and other drugs. Certain drugs are somewhat more effective in one type of The treatment of epilepsy of all types can be divided into four parts: seizure than in another, and it is necessary to use the proper drugs the use of antiepileptic drugs, the surgical excision of epileptic foci in optimum dosages for different circumstances. Initially, only one and other surgical measures, the removal of causative and precip- drug should be used and the dosage increased until sustained ther- short itating factors, and the regulation of physical and mental activity. apeutic levels have been attained. If seizures are not controlled by stand
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cap height Table 16-6 Table 16-8 base of text Choices of antiepileptic drugs by type of adult seizure Combination antiepileptic regimens for refractory seizures disorder COMBINATION INDICATION SEIZURE TYPE INITIAL CHOICE SECOND LINE Valproate and lamotrigine or Partial or generalized seizures Tonic-clonic Phenytoin, Lamotrigine, levetiracetam carbamazepine, oxcarbazepine Valproate and ethosuximide Generalized absence valproate Carbamazepine and valproate Complex partial seizures Myoclonic Valproate Lamotrigine Vigabatrin and lamotrigine or Partial seizures Partial Carbamazepine, Valporate, tiagabine phenytoin lamotrigine, Topiramate and lamotrigine Numerous types oxcarbazine or levetiracetam Absence Valproate Ethosuximide, lamotrigine SOURCE: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. Oxford, England, Health Press, 2001. Unclassifiable Valproate Lamotrigine
SOURCE: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. The therapeutic dose for any given patient must be deter- Oxford, England, Health Press, 2001. mined, to some extent, by trial and error and by measurement of serum levels, as described below. Not uncommonly a drug is dis- the first drug, a different drug should be tried, but frequent shifting carded as being ineffective, when a slight increase in dosage would of drugs is not advisable; each should be given an adequate trial have led to suppression of the attacks. It is, however, also an error before another is substituted. A general approach to the choice of to administer a drug to the point where the patient is so dull and drug in certain common forms of epilepsy is given in Tables 16-6 stupefied that the toxic effects are more incapacitating than the for adults and 16-7 for children, but it must be noted that there are seizures. It is highly doubtful that prolonged administration of an- a number of drugs that may be appropriate in each circumstance. ticonvulsant medication is a factor in the development of the mental A guide to various combinations of drugs that are helpful in re- deterioration that occurs in a small percentage of patients with con- fractory cases is given in Table 16-8. In changing medication, the vulsive seizures. In fact, improvement in mentation more often oc- dosage of the new drug should be increased gradually to an opti- curs following control of the seizures by the proper dosage of ap- mum level while the dosage of the old drug is gradually decreased; propriate antiepileptic drugs. the sudden withdrawal of a drug may lead to an increase in seizure The management of seizures with drugs is greatly facilitated frequency or status epilepticus, even though a new drug has been by having patients chart their daily medication and the number, substituted. If seizures are still not controlled, a second drug can time, and circumstances of seizures. Some patients find it helpful then be added. Seldom if ever are more than two drugs necessary; to use a dispenser that is filled on Sunday, for example, with suf- the physician should make an effort to succeed with one drug and ficient medication to last the week. This indicates to the patient with no more than two given in adequate dosage. Once an anti- whether a dose had been missed and whether the supply of medi- convulsant or a combination of anticonvulsants is found to be ef- cations is running low. fective, their use in most cases should be maintained for a period The proper use of anticonvulsant drugs is considerably en- of years, or indefinitely if circumstances justify their long-term use. hanced by the measurement of their serum levels. The concentra- tions of almost all the commonly used drugs can be measured on Table 16-7 a single specimen by immunoassay or by the older gas-liquid chro- Choices of antiepileptic drugs in childhood seizure disorders matography method. These measurements are helpful in regulating dosage, detecting irregular drug intake, identifying the toxic agent SEIZURE INITIAL in patients taking more than one drug, and assuring patient com- TYPE CHOICE SECOND THIRD pliance. Blood for serum levels is ideally drawn in the morning before breakfast and the first ingestion of anticonvulsants (“trough Tonic- Valproate, Lamotrigine, Phenytoin levels”), a practice that introduces consistency in the measurement clonic carbamazepine oxcarbazine of drug concentrations. Myoclonic Valproate Lamotrigine Phenobarbital, The effective serum levels for each of the commonly used clobazam anticonvulsant drugs are indicated in Table 16-5. The upper and Absence Valproate Lamotrigine, Clobazam lower levels of the “therapeutic range” are not to be regarded as ethosuximide immutable limits within which the serum values must fit. In some Partial Carbamazepine, Valproate, Lamotrigine, patients, seizures are controlled at serum levels below the thera- phenytoin gabapentin, vigabatrin, peutic range; in others, the seizures continue despite serum values oxcarbazine topiramate within this range. In the latter patients, seizures are sometimes con- Infantle Vigabatrin, Valproate Lamotrigine trolled by raising levels above the therapeutic range but not to the spasms cortico- point of producing clinical toxicity. In general, higher serum con- steroids centrations of drugs are necessary for the control of simple or com- Lennox- Valproate Topiramate, Felbamate plex partial seizures than for the control of tonic-clonic seizures Gastaut lamotrigine alone. It is to be noted that the blood level is not a precise measure
SOURCE: Adapted by permission from Brodie MJ, Schachter SC. Epilepsy, 2nd ed. of the amount of drug entering the brain, because—in the case of short Oxford, England, Health Press, 2001. the most widely used anticonvulsants—the larger proportion of stand
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cap height drug is bound to albumin and does not penetrate nervous tissue. renal failure, serum levels are not an accurate guide to therapy, and base of text Laboratory measurements of the serum concentration, however, de- the goal should be to attain free phenytoin concentrations of 1 to tect only the protein-bound fraction. In patients who are malnour- 2 mg/mL. In addition, uremia causes the accumulation of phenytoin ished or chronically ill or who have a constitutional reduction in metabolites, which are measured with the parent drug by enzyme- proteins, this may lead to intoxication at low total serum levels. multiplied immunoassay techniques. In patients who are being di- Certain anticonvulsants also have active metabolites that may pro- alyzed, total blood levels of phenytoin tend to be low because of duce toxicity but are not measured by methods ordinarily used to decreased protein binding; in this situation it is also necessary to determine serum concentrations of antiepileptic drugs. This is par- track free (unbound) phenytoin levels. Because dialysis removes ticularly true for the epoxide of carbamazepine. The situation may phenobarbital and ethosuximide, dosage of these drugs may have be further complicated by interactions between one anticonvulsant to be increased. Decreased phenytoin levels are also known to oc- and the metabolites of another, as, for example, the inhibition of cur during viral illnesses, and supplementary doses are occasionally epoxide hydrolase by valproic acid, leading to toxicity through the necessary. buildup of carbamazepine epoxide. In circumstances of unex- Once an effective anticonvulsant regimen has been established, plained toxicity in the face of conventionally obtained serum levels it must usually be continued for many years. Because of the long-term that are normal, it is therefore important to measure the levels of toxic effects of such a regimen, many neurologists choose not to in- free drug and the concentration of active metabolites by chromato- stitute anticonvulsant therapy after the occurrence of a single gener- graphic techniques. Drugs in common use for which tests of serum alized seizure in an otherwise normal child or adult (normal EEG and levels are not easily available include levetiracetam, lamotrigine, MRI and no family history of seizures). Our more conservative ap- topiramate, tiagabine, gabapentin and others; this requires an em- proach of administering an anticonvulsant for 6 to 12 months and then piric dosing schedule based on recommended amounts and dose re-evaluating the patient has already been mentioned. escalations for each age group. Finally, the pharmacokinetics of each drug plays a role in Discontinuation of Anticonvulsants Withdrawal of anticonvul- toxicity and the serum level that is achieved with each alteration sant drugs may be undertaken in patients who have been free of in the dose. This is particularly true of phenytoin, which has non- seizures for a prolonged period. There are few firm rules to guide linear kinetics once serum concentrations reach 10 mg/mL, as the the physician in this decision. A safe plan, applicable to most forms result of saturation of liver enzymatic capacity. For this reason, the of epilepsy, is to obtain an EEG whenever withdrawal of medica- typical increase in dose from 300 to 400 mg daily often results in tion is contemplated. We have taken the approach that if the tracing a disproportionate elevation of the serum level and toxic side ef- is abnormal by way of showing paroxysmal activity, it is generally fects. These elevations are also accompanied by a prolongation of better to continue treatment. A prospective study by Callaghan and the serum half-life, which increases the time to reach a steady-state colleagues has shown that in patients who had been seizure-free phenytoin concentration after dosage adjustments. Contrariwise, during 2 years of treatment with a single drug, one-third relapsed carbamazepine is known to induce its own metabolism, so that after discontinuation of the drug, and this relapse rate was much doses adequate to control seizures at the outset of therapy are no the same in adults and children and whether the drug was reduced longer effective several weeks later. over a period of weeks or months. The relapse rate was lower in Always to be considered in the use of an antiepileptic drug, patients with absence and generalized-onset seizures than in those as already mentioned, is its possible interactions with other drugs. with complex partial seizures and secondary generalization. A re- Many such interactions have been demonstrated, but only a few cent study by Specchio and colleagues gave results similar to those are of clinical significance, requiring adjustment of drug dosages of the large Medical Research Council Antiepileptic Drug With- (Kutt). Important drugs in this respect are chloramphenicol, which drawal Study—namely, that after 2 years on a single anticonvul- causes the accumulation of phenytoin and phenobarbital, and eryth- sant during which no seizures had occurred, the rate of relapse was romycin, which causes the accumulation of carbamazepine. Ant- 40 percent 2 1/2 years later and 50 percent at 5 years after discon- acids reduce the blood phenytoin concentration, whereas cimeti- tinuation; this compared to the seizure recurrence rate of 20 percent dine does the opposite. Salicylates may reduce the plasma levels for patients remaining on medication. Other authors have suggested of anticonvulsant drugs. Among anticonvulsant drugs, valproate that a longer seizure-free period is associated with a lesser rate of often leads to accumulation of phenytoin and of phenobarbital by relapse (see reviews of Todt and of Pedley and comments above, displacing them from serum proteins; equally important, warfarin under “Focal or Generalized Seizures in Late Adult Life”). Patients levels are decreased by the addition of phenobarbital or carbama- with juvenile myoclonic epilepsy, even those with long seizure- zepine and may be increased by phenytoin. Enzyme-inducing drugs free periods, should probably continue with medication lifelong, such as phenytoin, carbamazepine, and barbiturates can greatly in- but there have been no thorough studies to our knowledge to sup- crease the chance of breakthrough menstrual bleeding in women port this dictum. The appropriate duration of treatment for post- taking oral contraceptives, and adjustments in the amount of estra- infarction epilepsy has not been studied, and most neurologists con- diol must be made. tinue to use one drug indefinitely. Interestingly, epilepsy caused Hepatic failure can seriously affect antiepileptic anticonvul- by military brain wounds tends to wane in frequency or to disap- sant drug concentrations, since most of these drugs are metabolized pear in 20 to 30 years, then no longer requiring treatment in the liver. Serum levels must be checked frequently, and if there (Caveness). is hypoalbuminemia, it is advisable to obtain free drug levels for reasons just mentioned. Renal failure has only an indirect effect on The Use of Specific Drugs in Treatment the concentrations of the commonly used anticonvulsants, but some of Seizures newer agents, such as vigabatrin and gabapentin, are excreted through the kidneys. The main renal effects have to do with alter- General Comments Phenytoin, carbamazepine, and valproate short ations in protein binding that are induced by uremia. In end-stage are more or less equally effective in the treatment of both gener- stand
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cap height alized and partial seizures (see Table 16-5 for typical initial dos- established. Hyponatremia has been reported in 3 percent of pa- base of text ages). Valproate is probably less effective in the treatment of com- tients taking the latter drug. Should drowsiness or increased seizure plex partial seizures. The first two of these drugs putatively act by frequency occur, this complication should be suspected. blocking sodium channels, thus preventing abnormal neuronal fir- Valproate All preparations of this drug may be occasionally hep- ing and seizure spread. atotoxic, an adverse effect that is usually (but not invariably) lim- Since carbamazepine has somewhat fewer side effects, it is ited to children 2 years of age and younger. The use of valproate preferred as the initial drug by many neurologists, but phenytoin with hepatic enzyme–inducing drugs increases the risk of liver and valproate have very similar therapeutic and side-effect profiles. toxicity. However, mild elevations of serum ammonia and mild Carbamazepine and valproate are probably preferable to phenytoin impairments of liver function tests in an adult do not require dis- for epileptic children because they do not coarsen facial features continuation of the drug. An increasingly emphasized problem with and do not produce gum hypertrophy or breast enlargement. In valproate has been weight gain during the first months of therapy. many cases, phenytoin or carbamazepine alone will control the In one study there was an average addition of 5.8 kg, and even seizures. If not, the use of valproate (which facilitates GABA ac- more in those disposed to obesity. In addition, menstrual irregu- tivity) alone or the combined use of phenytoin and carbamazepine larities and polycystic ovarian syndrome may appear in young produces better control. In others, the addition of valproate to car- women taking the drug, perhaps as a consequence of the afore- bamazepine may prove effective. Because of the high incidence of mentioned weight gain. myoclonic epilepsy in adolescence, it has been our practice to use An intravenous form of valproate is available. The maximum valproate as the first drug in this age group. Weight gain and men- recommended rate of administration is 20 mg/min. strual irregularities (see below) during the period of initiation of Phenobarbital Introduced as an antiepileptic drug in 1912, phe- valproate may also figure into the decision regarding the choice of nobarbital is still highly effective, but because of its toxic effects— initial drug for otherwise uncomplicated seizures in women. drowsiness and mental dullness, nystagmus, and staggering—is Finally, it should be said that most of the commonly used seldom used as a first-line drug. The adverse effects of primidone antiepileptic drugs cause, to varying degrees, a decrease in bone are much the same. Both drugs may provoke behavioral problems density and an increased risk of fracture from osteoporosis in older in retarded children. It is still used to advantage as an adjunctive patients, particularly in women. Several mechanisms are probably anticonvulsant and as primary therapy in infantile seizures. active, among them, induction of the cytochrome P450 system, Newer and Ancillary Antiepileptic Drugs Lamotrigine closely which enzymatically degrades vitamin D. No specific recommen- resembles phenytoin in its antiseizure activity and toxicity and is dations have been offered to counteract this effect of bone loss. thought to have less risk of teratogenic effects, as mentioned below. Calcium supplements or one of the bisphosphonates are advised if It functions by selectively blocking the slow sodium channel, there is no contraindication. thereby preventing the release of the excitatory transmitters gluta- Phenytoin Both oral and intravenous forms are available. Rash, mate and aspartate. It is effective as a first-line and adjunctive drug fever, lymphadenopathy, eosinophilia and other blood dyscrasias, for generalized and focal seizures and may be an alternative to and polyarteritis are manifestations of an idiosyncratic phenytoin valproate in young women because it does not provoke weight gain hypersensitivity; their occurrence calls for discontinuation of the and ovarian problems. The main limitation to its use has been a medication. Overdose with phenytoin causes ataxia, diplopia, and serious rash in about 1 percent of patients, always requiring dis- stupor. The prolonged use of phenytoin often leads to hirsutism continuation of the drug, and lesser dermatologic eruptions in 12 (mainly in young girls), hypertrophy of gums, and coarsening of percent. It should be pointed out that certain registries have re- facial features in children. Chronic phenytoin use over several dec- ported far lower rates. The slow introduction of the medication may ades may occasionally be associated with peripheral neuropathy reduce the incidence of drug eruptions (see below). Rare cases of and probably with a form of cerebellar degeneration (Lindvall and reversible chorea have been reported, especially with the concur- Nilsson); it is not clear if these are strictly dose-related effects or rent use of phenytoin. Combined use with valproate greatly in- if there is an idiosyncratic reaction. An antifolate effect on blood creases the serum level of lamotrigine. and interference with vitamin K metabolism have also been re- Levetiracetam is a novel sodium channel blocker that has been ported, for which reason pregnant women taking phenytoin should useful in the treatment of partial seizures, mainly as an adjunctive drug. be given vitamin K before delivery and the newborn infant should It is very well tolerated if initiated slowly but produces considerable receive vitamin K as well to prevent bleeding. Phenytoin should sleepiness and dizziness otherwise and if used at high doses. There not be used together with disulfiram (Antabuse), chloramphenicol, are no important interactions with other antiepileptic drugs. sulfamethizole, phenylbutazone, or cyclophosphamide, and the use Felbamate, a drug similar to meprobamate, has shown prom- of either phenobarbital or phenytoin is not advisable in patients ise as an adjunctive form of treatment of generalized seizures, com- receiving warfarin (Coumadin) because of the undesirable inter- plex partial seizures, and Lennox-Gastaut syndrome, but its use has actions already described. Choreoathetosis is a rare idiosyncratic been greatly limited because of the rare occurrence of bone marrow side effect. suppression and liver failure. Carbamazepine This drug causes many of the same side effects Two other drugs, gabapentin and vigabatrin,weresynthesized as phenytoin, but to a slightly lesser degree. Leukopenia is com- specifically to enhance the intrinsic inhibitory system of gamma- mon, and there have been rare instances of pancytopenia, hypo- aminobutyric acid (GABA) in the brain. Gabapentin is chemically natremia, and diabetes insipidus as idiosyncratic reactions. It is similar to GABA, but actually its anticonvulsant mechanism is not essential, therefore, that a complete blood count be done before known. It is moderately effective in partial and secondary general- treatment is instituted and that the white cell count be checked ized seizures and has the advantage of not being metabolized by the regularly. A more recently introduced analogue of carbamazepine liver. Vigabatrin and the related drugs progabide and tiagabine are oxcarbazepine is said to have even fewer of these side effects than inhibitors of GABA transaminase and are effective in the treatment short the parent drug, but its long-term therapeutic value still has to be of partial seizures and, to a lesser extent, primary generalized sei- stand
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cap height zures. Neither is bound to plasma protein, and they have the advan- epilepsy experts prefer to avoid the use of valproate during preg- base of text tage of few toxic effects and no known adverse drug interactions. nancy altogether. Also, these risks are greater in women taking Topiramate, another new antiepileptic agent, has much the more than one anticonvulsant, so that monotherapy is a desirable same mode of action and degree of effectiveness as tiagabine. It goal. Furthermore, the risk is disproportionately increased in fam- may cause serious dermatologic side effects, especially if used with ilies with a history of these defects. Some of the newer anticon- valproate, and appears to induce renal stones in 1.5 percent of pa- vulsants should probably be used cautiously until greater experi- tients. Angle-closure glaucoma has also been reported as a com- ence has been obtained. For example, claims have been made of plication. A minor problem has been the development of hyper- safety in this regard for lamotrigine and many specialists have chloremic metabolic acidosis. changed from the more conventional drugs to this one in women Ethosuximide (Zarontin) and valproate are equally effective who anticipate becoming pregnant. for the treatment of absence seizures, the latter one being used If a woman with seizure disorder has been off epilepsy medica- mainly in children more than 4 years of age. It is good practice, in tions for a time before getting pregnant and seizes during the preg- order to avoid excessive sleepiness, to begin with a single dose of nancy, the best choice of medications is probably phenytoin. Exposure 250 mg of ethosuximide per day and to increase it every week until of the fetus late in gestation poses few teratogenic risks. The special the optimum therapeutic effect is achieved. Methsuximide (Celon- case of eclamptic seizures is managed by infusion of magnesium. tin) is useful in individual cases where ethosuximide and valproate It should also be mentioned that most anticonvulsants induce have failed. In patients with benign absence attacks that are asso- the activity of hepatic enzymes, and this may result in the failure ciated with photosensitivity, myoclonus, and clonic-tonic-clonic of contraceptive pills due to the accelerated metabolism of steroids. seizures (including juvenile myoclonic epilepsy), valproate is the Epileptic women of childbearing age should be advised that higher drug of choice. Valproate is particularly useful in children who doses of the estradiol component are required. have both absence and grand mal attacks, since the use of this drug Skin Eruptions from Antiepileptic Drugs As mentioned in the alone often permits the control of both types of seizure. The con- discussion above, these are the most common idiosyncratic reac- current use of valproate and clonazepam has been known to pro- tions to the drugs used to treat epilepsy. The aromatic compounds duce absence status. (phenytoin, carbamazepine, phenobarbital, primidone, and lamo- Teratogenic Effects of Antiepileptic Medications Since it is es- trigine) are the ones most often responsible. Furthermore, there is sential to prevent convulsions in the pregnant epileptic woman, a high degree of cross-reactivity within this group, particularly anticonvulsant medication should not be discontinued or arbitrarily between phenytoin, carbamazepine and phenobarbital, and possibly reduced, particularly if there have been a number of convulsions lamotrigine. The problem arises most often in the first month of in the recent past. The conventional drugs (phenytoin, carbama- use. The typical eruption is maculopapular, mainly on the trunk; it zepine, phenobarbital, valproate) are all appropriately tolerated in usually resolves within days of discontinuing the medication. More pregnancy. Plasma levels of most anticonvulsant drugs, both the severe rashes may develop, sometimes taking the form of erythema free and protein-bound fractions, fall slightly in pregnancy and are multiforme and Stevens-Johnson syndrome, or even toxic epider- cleared more rapidly from the blood. The main practical issue is mal necrolysis. A rare hypersensitivity syndrome is one of high the potential teratogenicity of many of the anticonvulsant drugs. fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and The most common recorded teratogenic effects has been cleft lip hepatitis (nephritis) may follow. and cleft palate, but infrequently a subtle facial dysmorphism (“fe- If any of these reactions require that one of the aromatic drugs tal anticonvulsant syndrome”), similar to the fetal alcohol syn- be replaced, valproate, gabapentin, topiramate, or levetiracetam are drome, has also been described. In general, the risk of major con- reasonable substitutes, depending, of course, on the nature of the genital defects is low; it increases to 4 to 5 percent in women taking seizures. anticonvulsant drugs during pregnancy, in comparison to 2 to 3 Treatment of Seizures in the Neonate Treatment of the special percent in the overall population of pregnant women. These statis- types of convulsions in the neonatal period and in infancy and tics are essentially confirmed in the large study by Holmes and childhood is discussed by Fenichel and by Volpe. In general, phe- colleagues, conducted among several Boston hospitals. When all nobarbital is preferred for seizure control in infancy. types of malformations were included, both major and minor, 20 Probably the form of epilepsy that is most difficult to treat is percent of infants born to mothers who took anticonvulsants during the childhood Lennox-Gastaut syndrome. Some of these patients pregnancy showed abnormalities compared to 9 percent of mothers have as many as 50 or more seizures per day, and every combi- who had not taken medications. However, similar to other large nation of anticonvulsant medications may have no effect. Valproic surveys, major malformations appeared in only 5 percent of infants acid (900 to 2400 mg/day) will reduce the frequency of spells in exposed to anticonvulsants, in contrast to 2 percent in the nonex- approximately half the cases. The newer drugs—lamotrigine, to- posed. These authors identified “midface hypoplasia” (shortened piramate, vigabatrin—are each beneficial in about 25 percent of nose, philtrum, or inner canthal distance) and finger hypoplasia as cases. Clonazepam also has had limited success. characteristic of anticonvulsant exposure; these changes were In the treatment of infantile spasms, ACTH or adrenal corti- found in 13 and 8 percent of exposed infants, respectively. The costeroids have been effective, but vigabatrin is now found to be infants born of a group of women with epilepsy who had not taken as effective, including in patients with underlying tuberous scle- anticonvulsants during pregnancy showed an overall rate of dys- rosis (see Elterman et al). morphic features comparable to that in control infants, but there was still a 2 to 3 percent rate of facial and finger hypoplasia. This Status Epilepticus risk is shared more or less equally by all the major anticonvulsants. The risk of neural tube defects is also slightly increased by Recurrent generalized convulsions at a frequency that prevents re- anticonvulsants, and greatest is for the use of valproate; it can be gaining of consciousness in the interval between seizures (grand short reduced by giving folate before pregnancy has begun, but some mal status) constitute the most serious therapeutic problem (an stand
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cap height overall mortality of 20 to 30 percent, according to Towne and col- tablished. A large-bore intravenous line is inserted; blood is drawn base of text leagues, but probably lower in recent years). Most patients who die for glucose, blood urea nitrogen, electrolytes, and a metabolic and of epilepsy do so because of uncontrolled seizures of this type, drug screen. A normal saline infusion is begun and a bolus of complicated by the effects of the underlying illness or an injury glucose is given (with thiamine if malnutrition and alcoholism are sustained as a result of a seizure. Rising temperature, acidosis, hy- factors). potension, and renal failure from myoglobinuria is a sequence of To rapidly suppress the seizures, diazepam is given intra- life-threatening events that may be encountered in cases of status venously at a rate of about 2 mg/min until the seizures stop or a epilepticus. Prolonged convulsive status (for longer than 30 min) total of 20 mg has been given. Or lorazepam, 0.1 mg/kg given by also carries a risk of serious neurologic sequelae (“epileptic en- intravenous push at a rate not to exceed 2 mg/min, may be admin- cephalopathy”). The MRI during and for days after a bout of status istered, being marginally more effective than diazepam because epilepticus frequently shows signal abnormalities in the region of lorazepam putatively has a longer duration of action in the CNS a focal seizure or in the hippocampi, most often reversible, but we (see Tables 16-2 and 16-9). have had several such patients who awakened and were left in a Immediately thereafter, a loading dose (15 to 18 mg/kg) of permanent amnesic state. The MRI changes are most evident in phenytoin is administered by vein at a rate of less than 50 mg/min. FLAIR sequences. With regard to acute medical complications, More rapid administration risks hypotension and heart block; it is from time to time a case of neurogenic pulmonary edema is en- therefore recommended that the blood pressure and electrocardio- countered during or just after the convulsions, and some patients gram be monitored during the infusion. Phenytoin must be given may become extremely hypertensive, then making it difficult to through a freely running line with normal saline (it precipitates in distinguish the syndrome from hypertensive encephalopathy. other fluids) and should not be injected intramuscularly. A large Treatment (Table 16-9) The many regimens that have been pro- study by Treiman and colleagues has demonstrated the superiority posed for the treatment of status attest to the fact that no one of of using lorazepam instead of phenytoin as the first drug to control them is altogether satisfactory and none is clearly superior (Trei- status, but this is not surprising considering the longer latency of man et al). The present authors have had the most success with the action of phenytoin. Alldredge and colleagues have shown that following program: when the patient is first seen, an initial assess- diazepines can even be administered by paramedical workers with ment of cardiorespiratory function is made and an oral airway es- good effect in status epilepticus, terminating the seizures in about half of these patients. Nonetheless, a long-acting anticonvulsant such as phenytoin is given immediately after diazepam has con- Table 16-9 trolled the initial seizures. An alternative is the water-soluble drug Approach to the treatment of status epilepticus in adults fosphenytoin, which is administered in the same doses as phenytoin (see text) but can be injected at twice the maximum rate. Moreover, it can be given intramuscularly in cases where venous access is difficult. Initial assessment However, the delay in hepatic conversion of fosphenytoin to active Assure adequate ventilation, oxygenation, blood pressure phenytoin makes the latency of clinical effect approximately the Intubate if necessary, based on low oxygen saturation and same for both drugs. labored breathing In an epileptic patient known to be taking anticonvulsants Insert intravenous line chronically but in whom the serum level of drug is unknown, it is Administer glucose and thiamine in appropriate cirumstances probably best to administer the full recommended dose of phenyt- Send toxic screen oin or fosphenytoin. If it can be established that the serum phe- Assess quickly for cranial and cervical injury if onset of nytoin is above 10 mg/mL, a lower loading dose is advisable. If seizures is unwitnessed seizures continue, an additional 5 mg/kg is indicated. If this fails Immediate suppression of convulsions to suppress the seizures and status has persisted for 20 to 30 min, Lorazepam or diazepam, 2 to 4 mg/min IV to a total dose of an endotracheal tube should be inserted and O administered. 10 to 15 mg with blood pressure monitoring when higher 2 Several approaches have been suggested to control status that rates or doses are used persists after these efforts. The conventional and still dependable Initiation or reloading with anticonvulsants one is infusion of either thiopental, starting with 5 mg/kg, or phe- Phenytoin 15–18 mg/kg IV at 25–50 mg/min in normal saline nobarbital, at a rate of 100 mg/min until the seizures stop or a total or fosphenytoin at 50 to 75 mg/min dose of 20 mg/kg is reached. In our experience, a long period of General anesthetic doses of medication for persistent status stupor must be anticipated after seizure control is obtained, but epilepticus some epileptologists still prefer this as the initial treatment. Hy- Midazolam 0.2-mg/kg loading dose followed by infusion at potension often limits the continued use of the barbiturates, but 0.1 to 0.4 mg/kg/h or propofol 2 mg/kg/h Parviainen and colleagues were able to manage this problem by Further treatment if convulsions or electrographic seizures fluid infusions, dopamine, and neosynephrine (we tend to depend persist after several hours on neosynephrine). Alternatively, at this stage, we have resorted to May add valproate or phenobarbital 10 mg/min to total dose of the approach of Kumar and Bleck, of giving high doses of mid- 20 mg/kg as additional anticonvulsants intravenously, or azolam (0.2 mg/kg loading dose followed by an infusion of 0.1 to carbamazepine or levetiracetam by nasogastric tube if there 0.4 mg/kg/h as determined by clinical and EEG monitoring). If is gastric and bowel activity seizures continue, the dose can be raised as blood pressure permits. Consider neuromuscular paralysis with EEG monitoring if We have had occasion to use in excess of 20 mg/h because of a convulsions persist diminishing effect over days. This regimen of midazolam and phe- Pentobarbital 10 mg/kg/h nytoin may be maintained for several days without major ill effect short Inhalational anesthetics (isoflurane) in previously healthy patients. Propofol given in a bolus of stand
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cap height 2 mg/kg and then as an intravenous drip of 2 to 8 mg/kg/h is an Petit mal status should be managed by intravenous lorazepam, base of text effective alternative to midazolam, but after 24 h the drug behaves valproic acid, or both, followed by ethosuximide. Nonconvulsive like a high dose of barbiturate and there may be difficulty due to status is treated along the lines of grand mal status, usually stopping hypotension. short of using anesthetic agents. If none of these measures controls the seizures, all medication except phenytoin should be discontinued and a more aggressive Surgical Treatment of Epilepsy approach taken to subdue all brain electrical activity by the use of general anesthesia. The preferred medications for this purpose have The surgical excision of epileptic foci in simple and complex partial been pentobarbital and propofol, which, despite their poor record epilepsies that have not responded to intensive and prolonged med- as primary anticonvulsants, are easier to manage than the alterna- ical therapy is being used with increasing effectiveness in a grow- tive inhalational anesthetic agents. An initial intravenous dose of ing number of specialized epilepsy units. At these centers, it has 5 mg/kg pentobarbital or 2 mg/kg propofol is given slowly to in- been estimated that approximately 25 percent of all patients with duce an EEG burst-suppression pattern, which is then maintained epilepsy are candidates for surgical therapy and more than half of by the administration of 0.5 to 2 mg/kg/h pentobarbital or up to 10 these may benefit from surgery. With increasing experience and mg/kg/h of propofol. Every 12 to 24 h, the rate of infusion is slowed standardized approaches, especially in patients with temporal lobe to determine whether the seizures have stopped. The experience of epilepsy, it has been suggested that many patients are waiting too Lowenstein and colleagues, like our own, is that most instances of long before the surgical option. A perspective that may promote status epilepticus that cannot be controlled with the standard anti- surgery in even more patients is the observation that about 60 per- convulsants and midazolam will respond to high doses of barbi- cent of patients with partial seizures will respond to a conventional turates or propofol, but that these infusions cause hypotension and anticonvulsant but that among the remainder, few will respond to cannot be carried out for long periods. the addition of a second or third drug. Should the seizures continue, either clinically or electrograph- To locate the discharging focus requires a careful analysis of ically, despite all these medications, one is justified in the assump- clinical and EEG findings, often including those obtained by long- tion that the convulsive tendency is so strong that it cannot be term video/EEG monitoring and, sometimes, intracranial EEG re- checked by reasonable quantities of anticonvulsants. A few patients cording by means of intraparenchymal depth electrodes, subdural in this predicament have survived and awakened, even at times with strip electrodes, and subdural grids. Recently, functional imaging minimal neurologic damage. Isoflurane (Forane) has been used in and specialized EEG analysis have been introduced to supplement these circumstances with good effect, as we have reported (Ropper these methods. et al), but the continuous administration of such inhalational agents The most favorable candidates for surgery are those with com- is impractical in most critical care units. Halothane has been inef- plex partial seizures and a unilateral temporal lobe focus, in whom fective as an anticonvulsant, but ether, although impractical, has in rates of cure and significant improvement approach 90 percent in the past been effective in some cases. In the end, in these patients some series, but overall, are probably closer to 50 percent after 5 with truly intractable status, one usually depends on phenytoin, years. A randomized trial conducted by Wiebe and colleagues gave 0.5 g, and phenobarbital, 0.4 g/day (smaller doses in infants and representative results after temporal lobectomy of 58 percent of 40 children, as shown in Tables 16-9), and on measures that safeguard carefully studied patients remaining seizure-free after 1 year, in the patient’s vital functions. Valproate is available as an intrave- contrast to 8 percent on medication alone. Furthermore, as reported nous preparation, making it suitable for administration in status, by Yoon and colleagues, among those patients who remain free of but its potential role in this circumstance has not been extensively seizures for 1 year after surgery, over half are still free of seizures studied. after 10 years and most of the remainder had one or fewer episodes A word must be added concerning neuromuscular paralysis per year. It should be emphasized that most patients undergoing and continuous EEG monitoring in status epilepticus. With failure surgery in all these studies still require some anticonvulsant med- of aggressive anticonvulsant and anesthetic treatment, there may ication. Excision of cortical tissue outside of the temporal lobe be a temptation to paralyze all muscular activity, an effect easily accomplishes complete seizure-free states in about 50 percent. Tak- attained with drugs such as pancuronium, while neglecting the un- ing all seizure types together, only about 10 percent of patients derlying seizures. The use of such neuromuscular blocking drugs obtain no improvement at all and less than 5 percent are worse. without a concomitant attempt to suppress seizure activity is in- Other surgical procedures of value in selected cases are section advisable. If such measures are undertaken, continuous or frequent of the corpus callosum and hemispherectomy. The most encour- intermittent EEG monitoring is essential; this may also be also aging results with callosotomy have been obtained in the control helpful in the early stages of status epilepticus in that it guides the of intractable partial and secondarily generalized seizures, partic- dosages of anticonvulsants required to suppress the seizures. ularly when atonic drop attacks are the most disabling seizure type. In the related but less serious condition of acute repetitive Removal of the entire cortex of one hemisphere, in addition to the seizures, in which the patient awakens between fits, a diazepam amygdala and hippocampus, has been of value in children and also gel, which is well absorbed if given rectally, is available and has in some adults with severe and extensive unilateral cerebral disease been found useful in institutional and home care of epileptic pa- and intractable contralateral motor seizures and hemiplegia. Ras- tients, although it is quite expensive. A similar effect has been mussen encephalitis, Sturge-Weber disease, and large porenceph- attained by the nasal or buccal (transmucosal) administration of alic cysts at times fall into this category. Surgical, focused radia- midazolam, which is absorbed from these sites (5 mg/mL, 0.2 mg/ tion, or endovascular reduction of arteriovenous malformations kg nasally; 2 mL to 10 mg buccally). These approaches have found may reduce the frequency of seizures, but the results in this regard their main use in children with frequent seizures who live in su- are somewhat unpredictable (see Chap. 34). pervised environments, where a nurse or parent is available to ad- Driving and Epilepsy Only a few states in the United States and short minister the medication. most provinces of Canada mandate that physicians report patients stand
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cap height with seizures under their care to the state Motor Vehicle Bureau. mal a life as possible. Every effort should be made to keep children base of text Physicians should nonetheless counsel such a patient regarding the in school, and adults should be encouraged to work. Many com- obvious danger to himself and others if a seizure should occur (the munities have vocational rehabilitation centers and special social same holds for the risks of swimming unattended). What little data agencies for epileptics, and advantage should be taken of such fa- are available suggest that accidents caused directly by a seizure are cilities. rare and, in any case, 15 percent have been due to a first episode of seizure that could not have been anticipated. In some states Other Therapeutic Measures where a driver’s license has been suspended on the occurrence of a seizure, there is usually some provision for its reinstatement— Ketogenic Diet Since the 1920s, interest in this form of seizure such as a physician’s declaration that the patient is under medical control has varied, being revived periodically in centers caring for care and has been seizure-free for some period of time (usually 6 many children with intractable epilepsy. Despite the absence of months or 1 to 2 years). The Epilepsy Foundation website can be controlled studies showing its efficacy or a reasonable hypothesis consulted for updated information regarding restrictions on driving, for its mechanism, several trials in the first half of the twentieth and this serves as an excellent general resource for patients and century and again more recently have demonstrated a reduction in their families (www.efa.org). seizures in half of the patients, including handicapped children with severe and sometimes intractable fits. The regimen is initiated dur- Regulation of Physical and Mental ing hospitalization by starvation for a day or two in order to induce Activity ketosis, followed by a diet in which 80 to 90 percent of the calories are derived from fat (Vining). The difficulties in making such a The most important factors in seizure breakthrough, next to the diet palatable leads to its abandonment by about one-third of chil- abandonment of medication, are loss of sleep and abuse of alcohol dren and their families. A summary of experience from the nu- or other drugs. The need for moderation in the use of alcohol must merous trials of the ketogenic diet can be found in the review by be stressed, as well as the need to maintain regular hours of sleep. Lefevre and Aronson. They concluded that, despite the lack of a These seemingly anachronistic suggestions in an age of many avail- controlled trial, the diet can be effective in refractory cases of ep- able anticonvulsants are still valid. ilepsy in childhood. It has also been commented that some benefit A moderate amount of physical exercise is desirable. With persists even after the diet has been stopped. proper safeguards, even potentially more dangerous sports, such as swimming, may be permitted. However, a person with incom- Vagal Nerve Stimulation This experimental technique has pletely controlled epilepsy should not be allowed to drive an au- found favor in cases of intractable partial and secondarily gener- tomobile, operate unguarded machinery, climb ladders, or take tub alizing seizures. A pacemaker-like device is implanted in the an- baths behind locked doors; such a person should swim only in terior chest wall and stimulating electrodes are connected to the the company of a good swimmer and wear a life preserver when vagus at the left carotid bifurcation. The procedure is well tolerated boating. except for hoarseness in some cases. Several trials have demon- Psychosocial difficulties must be identified and addressed strated an average of one-quarter reduction in seizure frequency early. Simple advice and reassurance will frequently help to prevent among patients who were resistant to all manner of anticonvulsant or overcome the feelings of inferiority and self-consciousness of drugs (see Chadwick for a discussion of recent trials). The mech- many epileptic patients. Patients and their families may benefit anism by which vagal stimulation produces its effects is unclear, from more extensive counseling, and proper family attitudes should and its role in the management of seizures is still being defined. be cultivated. Oversolicitude and overprotection should be dis- Cerebellar stimulation has also been used in the control of seizures, couraged. It is important that the patient be allowed to live as nor- with no clear evidence of success.
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cap height MANFORD M, HART YM, SANDER JW, SHORVON SD: The national gen- flurane, halothane and nitrous oxide in status epilepticus. Ann Neurol 19: base of text eral practice study of epilepsy: The syndromic classification of the In- 98, 1986. ternational League Against Epilepsy, applied to epilepsy in a general SALANOVA V, ANDERMANN F, RASMUSSEN T, et al: Parietal lobe epi- population. Arch Neurol 49:801, 1992. lepsy. Clinical manifestations and outcome in 82 patients treated surgi- MATTSON RH, CRAMER JA, COLLINS JF, et al: Comparison of carba- cally between 1929 and 1988. Brain 118:607, 1995. mazepine, phenobarbital, phenytoin, and primidone in partial and sec- SCHEIBEL ME, SCHEIBEL AB: Hippocampal pathology in temporal lobe ondarily generalized tonic-clonic seizures. N Engl J Med 313:145, 1985. epilepsy: A Golgi survey, in Brazier MAB (ed): Epilepsy: Its Phenomena MEDICAL RESEARCH COUNCIL ANTIEPILEPTIC DRUG WITHDRAWAL in Man. New York, Academic Press, 1973, pp 315–357. STUDY GROUP. 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